ES2882782T3 - Benzoxaborol amide L-valinate derivatives for the treatment of parasitic diseases - Google Patents

Abstract

A compound selected from the group consisting of: (6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)- L-valinate; 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; 4,4-difluorocyclohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; and tetrahydro-2H-pyran-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof.

Description

DESCRIPTION

Benzoxaborole amide L-valinate derivatives for the treatment of parasitic diseases

Background of the invention

Trypanosomatids are a group of kinetoplastid protozoa that are distinguished by having a single flagellum. Trypanosomatids are responsible for diseases such as South American trypanosomiasis (Chagas disease) and African animal trypanosomiasis (AAT).

Chagas disease, caused by the protozoan parasite Trypanosoma cruzi, is endemic to many Latin American countries. The World Health Organization has estimated that between 16 and 18 million people are currently infected and 90 million are at risk of infection (WHO 2002, Schofield et al, 2006). The estimated global burden of disease is 649,000 disability-adjusted life years (the number of years of healthy life lost due to premature death and disability). Causing around 14,000 deaths a year, Chagas disease kills more people in Latin America than any other parasitic disease, including malaria.

T. cruzi is transmitted by several insect vectors that belong to the Reduviidae family. Transmission to humans depends on living conditions, as these insects inhabit mud and straw houses that are common in lower socioeconomic areas. The infection can also be acquired by consuming contaminated food, congenitally, or by blood transfusion or organ transplant. The acute phase of T. cruzi infection is usually controlled by the emerging immune response and is mild or asymptomatic and therefore often undetected. However, the vast majority of infected people fail to clear the infection and thus remain chronically infected; 30-40% of these will eventually develop life-threatening heart or gastrointestinal disease. Chronic Chagas remains an incurable disease, causing severe long-term disability or death in approximately one-third of those infected. In addition, the disability caused by chronic Chagas disease has a great social and economic impact, including unemployment and decreased earning capacity. According to a 2012 estimate from the World Health Organization, more than 500,000 disability-adjusted life years (DALYs) were attributable to Chagas disease (Moncayo A, Ortiz Yanine M. Ann Trop Med Parasitol. 2006; 100: 663 -677). In addition to lost productivity, the medical costs of treating infected people who develop serious chronic heart or digestive problems are high.

It has long been established that T. cruzi can infect dogs, particularly those housed outdoors, in the southern United States, Central and South America. A recent study in Texas suggested that shelter dogs serve as a good indicator for all dogs, finding that -9% of shelter dogs tested in Texas harbored T. cruzi. In Texas, T. cruzi infection in dogs is considered a "notifiable condition"; any dog found to be harboring the parasite should be reported to the Texas Department of State Health Services. As there is no approved treatment for Chagas disease in dogs, the animals can be euthanized.

African animal trypanosomiasis is endemic in 37 African countries, affects livestock on 10 million km2 of arable land, and remains a major constraint to agricultural production, particularly livestock in these areas. Trypanosomiasis can also be prevented in Central and South America. The disease is mainly caused by three protozoan parasites: Trypanosoma congolense ( T. congolense), T. vivax, and T. evansi, and is vectored by the tsetse fly and, for T. .evansi, is also mechanically transferred from one host to another by Tabanus. spp. of fly bite. The disease is characterized by progressive anemia, loss of condition, and lassitude with recurrent episodes of fever and parasitaemia. The severity of the disease varies according to the species of Trypanosoma, the breed, the age and the health status of the infected animal. In cattle, this infection causes high mortality and morbidity with significant negative effects on growth, lactation, weaning age and weight. In draft animals, power, speed, and distance traveled per day are also affected. Trypanosomiasis has a significant economic impact on livestock production in Africa and, if left untreated, usually results in a chronic disease with high mortality. Trypanosomiasis has been estimated to cost African ranchers between $2 billion and $5 billion a year. In the absence of vaccines, control of this disease has long focused on chemotherapy and vector control. For many decades, only three compounds, diminazene, isometamidium, and homidium, have been widely used as trypanocides, and consequently drug resistance in target pathogens has become a major concern. New chemical entities with novel mechanisms of action are urgently needed to combat these diseases.

WO2010/045503 describes compounds useful for treating protozoan infections.

Dazhong Ding, et al; "Discovery of Novel Benzoxaborol-Based Potent Antitrypanosomal Agents"; ACS Med Chem Lett.

July 8, 2010; 1(4):165-169 disclose benzoxaborol antitrypanosomal agents that have in vivo efficacy in models of acute murine infection against Tryapnosoma brucei.

WO2015/097276 discloses compounds that are useful as microbial infections, especially fungal infections in plants.

Summary of the invention

In certain embodiments, the present invention provides a compound according to claim 1 or a pharmaceutically acceptable salt thereof.

Detailed description of certain embodiments

The present disclosure provides a compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

R1 is hydrogen or aliphatic C ^{1 to 6;}

R1a is hydrogen or aliphatic C ^{1 to 6;} or

R1 and R1a are taken together with the carbon atom to which they are attached to form an optionally substituted 3 to 6 membered spirocarbocyclic ring;

each R2 is independently hydrogen, -halogen, -OR, -NO ² , -CN, -SR, -N(R) ² , -C(O)R, -C(O)OR, -S(O)R, -S(O) ² R, -C(O)N(R) ² , -SO ² N(R) ² , -OC(O)R, -N(R)C(O)R, -N(R ) C (O) oR, -N (R) SO ² R, -OC (O) N (R) ^2, or an optionally substituted group selected from the group consisting of aliphatic C ^1-6 carbocyclyl monocyclic saturated or partially unsaturated from 3 to 6 members;

R3 is hydrogen or optionally substituted ^{C 1-6 aliphatic;}

R4 is hydrogen, a side chain of natural or unnatural amino acid, or an optionally substituted group selected from the group consisting of aliphatic C ^1-6 monocyclic carbocyclyl saturated or partially unsaturated 3 to 7 membered and phenyl; or

R3 and R4 are taken together with the carbon atom attached to R4 and the nitrogen atom attached to R3 to form an optionally substituted 3 to 6 membered heterocyclyl ring having 0-1 additional heteroatoms selected from oxygen, nitrogen or sulfur;

R5 is hydrogen or optionally substituted ^{C 1-6 aliphatic;} or

R4 and R5 are taken together with the carbon atom to which they are attached to form an optionally substituted ring selected from a 3 to 6 membered spiroheterocyclic ring having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur, and a monocyclic spirocarbocyclic ring. saturated or partially unsaturated from 3 to 6 members; L is a covalent bond or a straight or branched hydrocarbon chain, saturated or unsaturated C ^1-10 divalent, optionally substituted, in which one, two or three methylene units of L are replaced by -Cy- optionally independently -O -, -SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC (O)-, -N(R)C(O)-, -N(R)SO ² -, or -SO ² N(R)-;

wherein each -Cy- is independently an optionally substituted bivalent ring selected from the group consisting of phenylene, 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclylene, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5 to 6 membered heteroarylene having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 7 to 10 membered bicyclic saturated or partially unsaturated carbocyclylene, 8 to 10 membered bicyclic arylene, bicyclic heterocyclylene 7 to 10 membered saturated or partially unsaturated having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, and 7 to 10 membered bicyclic heteroarylene having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur;

R6 is hydrogen, -halogen, -OR, -NO ² , -CN, -SR, -N(R) ² , -C(O)R, -C(O)OR, -S(O)R, -S (O) ² R, -C(O)N(R) ² , -SO ² N(R) ² , -OC(O)R, -N(R)C(O)R, -N(R)C (O) oR, -N (R) SO ² R, -OC (O) n (r) ^2, an optionally substituted group selected from the group consisting of aliphatic C ^{1 to 6,} phenyl, carbocyclyl monocyclic saturated or partially unsaturated 3 to 7 membered, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5 to 6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 7 to 10 membered saturated or partially unsaturated bicyclic carbocyclyl, 8 to 10 membered bicyclic aryl, bicyclic heterocyclyl 7 to 10 membered saturated or partially unsaturated having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, 7 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and bridged bicyclic;

each R is independently hydrogen or optionally substituted ^{C 1-6 aliphatic;}

where when L is a covalent bond, R6 is other than -OR, -halogen, -NO ² , -CN, -SR, -N(R) ² , -S(O)R, -S(O) ² R , -SO ² N(R) ² , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)SO ² R, u - OC(O)N(R) ² ; Y

wherein when L is other than a covalent bond, it includes a carbon atom bonded to the carboxyl oxygen designated O*.

Definitions

For purposes of this invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, general principles of organic chemistry are described in "Organic Chemistry" , Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry", 5th Ed., Ed.: Smith, MB and March, J., John Wiley & Sons, New York: 2001.

Abbreviations used in this document have their conventional meaning within the chemical and biological arts. The chemical structures and formulas set forth herein are constructed in accordance with the standard chemical valence rules known in the chemical arts.

The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is either fully saturated or contains one or more unsaturating units, or a monocyclic or bicyclic hydrocarbon that is fully saturated or contains one or more unsaturating units, but is not aromatic (also referred to herein as "carbocyclyl,""cycloaliphatic," or "cycloalkyl"), having a single point of attachment to the structural unit of the molecule. Unless otherwise specified, aliphatic groups contain from 1 to 6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 5 aliphatic carbon atoms. In some embodiments, aliphatic groups contain from 1 to 4 aliphatic carbon atoms. In some embodiments, the aliphatic groups contain 1-3 aliphatic carbon atoms, and in still other embodiments, the aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocyclyl" or "cycloalkyl") refers to a hydrocarbon C ³ -C ⁷ monocyclic saturated or fully containing one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the structural unit of the molecule. Suitable aliphatic groups include, but are not limited to, substituted or unsubstituted linear or branched alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

As used herein, the term "bridged bicyclic" refers to any bicyclic, ie, carbocyclic or heterocyclic, saturated or partially unsaturated, ring system having at least one bridge. As defined by IUPAC, a "bridge" is an unbranched chain of atoms or an atom or valence bond connecting two bridgeheads, where a "bridgehead" is any atom in the backbone of the ring system that is bonded to three or more backbone atoms (excluding hydrogen). In some embodiments, a bridged bicyclic group has 7-12 ring members and 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Such bridged bicyclic groups are well known in the art and include those in which the group is attached to the structural unit of the molecule at any substitutable carbon or nitrogen atom. Unless otherwise specified, a bridged bicyclic group is optionally substituted with one or more substituents as indicated for aliphatic groups. Additionally or alternatively, any substitutable nitrogen of a bridged bicyclic group is optionally substituted.

The term "heteroatom" means one or more of oxygen, sulfur, nitrogen, phosphorus or silicon (including, any oxidized form of nitrogen, sulfur, phosphorus or silicon; the quaternized form of any basic nitrogen or; a substitutable nitrogen of a heterocyclic ring , for example N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR+ (as in N-substituted pyrrolidinyl)).

The term "unsaturated" as used herein means that a structural unit has one or more units of unsaturation.

As used herein, the term " ^{linear or branched, bivalent C 1-10} (or C ^1-6 , etc.) hydrocarbon chain" refers to bivalent alkylene, alkenylene, and alkynylene chains that are linear. or branched as defined herein.

The term "alkylene" refers to a bivalent alkyl group. An "alkylene chain" is a polymethylene group, ie, -(CH ² )n-, where n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2 or 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

The term "alkenylene" refers to a bivalent alkenyl group. A substituted alkenylene chain is a polymethylene group containing at least one double bond in which one or more hydrogen atoms are replaced by a substituent. Suitable substituents include those described below for a substituted aliphatic group.

The term "halogen" means F, Cl, Br or I.

The term "aryl" used alone or as part of a larger structural unit as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to 10 ring members. , wherein at least one ring of the system is aromatic and each ring of the system contains from three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In some embodiments, an 8-10 membered bicyclic aryl group is an optionally substituted naphthyl ring. In certain embodiments of the present invention, "aryl" refers to an aromatic ring system including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may have one or more substituents. Also included within the scope of the term "aryl", as used herein, is a group in which an aromatic ring is fused with one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthymidyl, phenanthridinyl, or tetrahydronaphthyl, and the like. .

The terms "heteroaryl" and "heteroar-", used alone or as part of a larger structural unit, for example, "heteroaralkyl" or "heteroaralkoxy", refer to groups having from 5 to 10 ring atoms, preferably 5, б, or 9 ring atoms; have 6, 10, or 14 shared n-electrons in a cyclic matrix; and having, in addition to carbon atoms, from one to five heteroatoms. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrizinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, wherein the radical or point of attachment is at the heteroaromatic ring. Non-limiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzothiazolyl, quinolyl, isoquinolyl, cinolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridininyl, phenazilyl, phenohydroquinisolylinyl, tetrahydroquinisolynyl, , and pyrido[2,3-b]-1,4-oxazin-3(4H)-one. A heteroaryl group can be mono or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted with a heteroaryl, wherein the alkyl and heteroaryl portions, independently, are optionally substituted.

As used herein, the terms "heterocyclyl", "heterocyclic radical" and "heterocyclic ring" are used interchangeably and refer to a stable 5-7 membered monocyclic or 7-10 membered bicyclic heterocyclic moiety that is saturated. or partially unsaturated and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in this context in reference to a ring atom, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur, or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl).

A heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms may be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenylpyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical" are used interchangeably herein and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, wherein the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group can be mono or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted with a heterocyclyl, wherein the alkyl and heterocyclyl portions are optionally substituted independently.

As used herein, the term "partially unsaturated" refers to a ring structural unit that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation, but is not intended to include aryl or heteroaryl moieties, as defined herein.

As used herein, the term "natural amino acid side chain group" refers to the side chain group of any of the 20 amino acids naturally found in proteins. sayings Natural amino acids include the nonpolar or hydrophobic amino acids, glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, and proline. Cysteine is sometimes classified as nonpolar or hydrophobic and other times as polar. Natural amino acids also include polar or hydrophilic amino acids, such as tyrosine, serine, threonine, aspartic acid (also known as aspartate, when charged), glutamic acid (also known as glutamate, when charged), asparagine, and glutamine. Certain polar or hydrophilic amino acids may have charged side chains. Such charged amino acids include lysine, arginine, and histidine. One skilled in the art would recognize that protection of a polar or hydrophilic amino acid side chain can render that amino acid nonpolar. For example, a properly protected tyrosine hydroxyl group can render that tyrosine nonpolar and hydrophobic by virtue of a hydroxyl protecting group.

As used herein, the term "unnatural amino acid side chain group" refers to the side chain group of amino acids not included in the list of 20 naturally occurring amino acids in proteins, as described above. Such amino acids include the D isomer of any of the 20 natural amino acids. Unnatural amino acids also include homoserine, ornithine, norleucine, and thyroxine. Other unnatural amino acid side chains are well known to those of skill in the art and include unnatural aliphatic side chains. Other unnatural amino acids include modified amino acids, including those that are N-alkylated, cyclized, phosphorylated, acetylated, amidated, azidylated, labeled, and the like. In some embodiments, an unnatural amino acid is a D-isomer. In some embodiments, an unnatural amino acid is an L-isomer.

As described herein, the compounds of the invention may, where specified, contain "optionally substituted" structural units. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated structural unit are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position in the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be the same or different at each position. Combinations of substituents contemplated by this invention are preferably those that result in the formation of stable or chemically feasible compounds. The term "stable" as used herein refers to compounds that are not substantially altered when subjected to conditions to allow their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed in this document.

Suitable monovalent substituents on a substitutable carbon atom of an "optionally substituted" group are independently halogen; -(CH ² ) ⁰ - ⁴ R°; -(CH ² ) ⁰ - ⁴ OR°; -O(CH ² ) ⁰ - ⁴ R°, -O-(CH ² ) ⁰ - ⁴ C(O)Or °; -(CH ² ) ⁰ - ⁴ CH(OR°) ² ; -(CH ² ) ⁰ - ⁴ SR°; - (CH ^{2) 0-4} Ph, which may be substituted with R °; -(CH ² ) ⁰ - ⁴ O(CH ² ) ⁰ - ¹ Ph which may be substituted with R°; -CH=CHPh, which may be substituted with R°; - (CH ^{2) 0-4} O (CH ^{2) 0-1} -pyridyl which may be substituted with R °; -NO ² ; -CN; -N3; -(CH2)0-4N(R°)2; -(CH2)0-4N(R°)C(O)R°; -N(R°)C(S)R°; -(CH2)0-4N(R°)C(O)NR°2; -N(R°)C(S)NR°2; -(CH2)0-4N(R°)C(O)OR°; -N(R°)N(R°)C(O)R°; -N(R°)N(R°)C(O)NR°2; -N(R°)N(R°)C(O)OR°; -(CH2)0-4C(O)R°; -C(S)R°; -(CH2)0-4C(O)OR°; -(CH2)0-4C(O)SR°; -(CH2)0-4C(O)OSiR°3; -(CH2)0-4OC(O)R°; -OC(O)(CH2)0-4SR°; -SC(S)SR°; -(CH2)0-4SC(O)R°; -(CH2)0-4C(O)NR°2; -C(S)NR°2; -C(S)SR°; -SC(S)SR°, -(CH2)0-4OC(O)NR°2; -C(O)N(OR°)R°; -C(O)C(O)R°; -C(O)CH2C(O)R°; -C(NOR°)R°; -(CH2)0-4SSR°; -(CH2)0-4S(O)2R°; -(CH2)0-4S(O)2OR°; -(CH2)0-4OS(O)2R°; -S(O)2NR°2; -(CH2)0-4S(O)R°; -N(R°)S(O)2NR°2; -N(R°)S(O)2R°; -N(OR°)R°; -C(NH)NR°2; -P(O)2R°; -P(O)R°2; -OP(O)R°2; -Op (O)(OR°) ² ; SiR° ³ ; -(C ^1-4 linear or branched alkylene)ON(R°) ² ; or - (C ^1-4 linear or branched) C (O) ON (R °) ² wherein each R ° may be substituted as defined below and is independently hydrogen, aliphatic C ^1-6, -CH ² Ph, -O(CH ² ) ⁰ - ¹ Ph, -CH ² -(5-6 membered heteroaryl ring), or a saturated, partially unsaturated, or 5-6 membered aryl ring having 0-4 independently selected heteroatoms of nitrogen, oxygen, or sulfur, or, without prejudice to the definition above, two independent occurrences of R°, taken together with their intervening atom(s), form a mono or bicyclic saturated, partially unsaturated, or 3-aryl ring. 12-membered having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

Suitable monovalent substituents on R° (or the ring formed by taking two independent occurrences of R° together with its intervening atoms) are independently halogen, -(CH ² ) ⁰ - ² R^ , -(haloR^), -(CH ² ) ⁰ - ² Oh , -(CH ² ) ⁰ - ² OR ,^ -(CH ² ) ⁰ - ² CH(OR-) ² ; -O(haloR-), -CN, -N ³ , -(CH ² ) ⁰ - ² C(O)R-, -(CH ² ) ⁰ - ² C(O)OH, -(CH ² ) ⁰ - ² C(O)OR-, -(CH ² ) ⁰ - ² SR-, -(CH ² ) ⁰ - ² SH, -(CH ² ) ⁰ - ² NH ² , -(CH ² ) ⁰ - ² NHR- , - (CH ^{2) 0-2} NR ^2, -NO ^2, -SiRVj, -OSiRVj, -C (O) SR- - (alkylene linear or branched -C ^1.4) C (O) oR, or-SSR ^ wherein each R is unsubstituted or where preceded by "halo" is only substituted by one or more halogens, and is independently selected from aliphatic C ^1-4, -CH ² Ph, -O (CH ^{2) 0} - ¹ Ph, or a 5-6 membered partially unsaturated or saturated aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur. Suitable divalent substituents on a saturated carbon atom of R° include =O and =S.

Suitable divalent substituents on a saturated carbon atom of an "optionally substituted" group include the following: =O, =S, =NNR* ² , =NNHC(O)R*, =NNHC(O)OR*, =NNHS (O) ² R*, =NR*, =NOR*, -O(C(R* ² ))m O-, or -S(C(R* ² )) ² - ³ S-, where each occurrence independent of R* is selected from hydrogen, C ^1-6 aliphatic which may be substituted as defined below, or an unsubstituted, saturated, partially unsaturated aryl or 5-6 membered aryl ring having 0-4 independently selected heteroatoms between nitrogen, oxygen or sulfur. Suitable divalent substituents that are attached to neighboring substitutable carbons of an "optionally substituted" include: -O(CR* ² ) ² - ³ O-, where each independent occurrence of R* is selected from hydrogen, aliphatic C ^ which may be substituted as defined below, or a partially saturated aryl ring unsaturated or unsubstituted 5-6 membered having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of R* include halogen, -R ,^ - (haloR^), -OH, -OR ,^ -O(haloR^), -CN, -C(O)OH, -C( O)OR^, -NH ² , -NHR^, -n R^ ² , or -NO ² , where each R^ is unsubstituted or when preceded by "halo" is substituted only with one or more halogens, and is independently aliphatic C ^1-4, -CH ² Ph, -O (CH ^{2) 0-1} Ph, or an aryl ring, saturated or partially unsaturated 5-6 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on a substitutable nitrogen of an "optionally substituted" group include -Rf , -NRf ² , -C(O)Rt, -C(O)ORt, -C(O)C(O)Rt, -C( O)CH ² C(O)Rt, -S(O^Rf , -S(O) ² NR^, -C(S)NR^, -C(NH)NR^, or -N(Rt)S( O) ² Rf ; where each Rf is independently hydrogen, C ^1-6 aliphatic which may be substituted as defined below, unsubstituted -OPh, or an unsubstituted 5-6 membered saturated or partially unsaturated aryl ring which has 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of Rf , taken together with its intermediate atom(s) form a partially saturated, mono- or bicyclic ring unsaturated or unsubstituted 3-12 membered aryl having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur.

Suitable substituents on the aliphatic group of Rf are independently halogen, -R^ , -(haloR^), -OH, -OR ,^ -O(haloR^), -CN, -C(O)OH, -C( O)OR^, -NH ² , -NHR^, -NR^, or -NO ² , where each R^ is unsubstituted or when preceded by "halo" is substituted with only one or more halogens, and is independently aliphatic C ^1-4, -CH ² Ph, -O (CH ^{2) 0-1} Ph, or an aryl ring, saturated or partially unsaturated 5-6 membered ring having 0-4 heteroatoms independently selected from nitrogen, oxygen or sulfur .

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which, within the scope of sound medical judgment, are suitable for use in contact with human and lower animal tissues without toxicity, irritation, or response. undue allergic reactions and are proportional to a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

In certain embodiments, neutral forms of compounds are regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner. In some embodiments, the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents.

Unless otherwise indicated, structures depicted herein are also intended to include all isomeric (eg, enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure; for example, the R and S configurations for each asymmetric center, Z and E double bond isomers, and Z and E conformational isomers. Thus, the individual stereochemical isomers, as well as the enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise indicated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Furthermore, unless otherwise indicated, the structures depicted herein are also intended to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures that include the substitution of hydrogen for deuterium or tritium, or the substitution of a carbon for a carbon enriched with 13C or 14C are within the scope of this invention. Such compounds are useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present invention.

The term "oxo" as used herein means an oxygen that is doubly bonded to a carbon atom, thus forming a carbonyl.

The symbol -", except when used as a bond to represent a mixed or unknown stereochemistry, indicates the point of attachment of a chemical moiety to the moiety of a molecule or chemical formula.

compounds

As described above, the compounds of the present disclosure are compounds of formula I:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R1a, R2, R3, R4, R5, R6, and L is as defined above and is described in classes and subclasses herein, both individually and in combination .

As used herein, unless otherwise indicated, references to Formula I also include all subgenera of Formula I defined and described herein (eg, Formulas II, III, III-a, IV, V, V a, Vb, VI-a, VI-b, VI-c, VI-d, VI-e, VI-f, VII-a, VII-b, VII-c, VIII-a, VIII-b , VIII-c, IX-a and IX-B).

It will be appreciated that the "O*" used in formula I is an oxygen atom, and the "*" is used herein to refer to connectivity to the L group.

In some embodiments, R1 and R1a are hydrogen. In some embodiments, R1 and R1a are methyl.

In some embodiments, R1 and R1a are taken together with the carbon atom to which they are attached to form an optionally substituted 3 to 6 membered spirocarbocyclic ring. In some embodiments, R1 and R1a are taken together with the carbon atom to which they are attached to form a 6-membered spirocarbocyclic ring. In some embodiments, R1 and R1a are taken together with the carbon atom to which they are attached to form a 5-membered spirocarbocyclic ring. In some embodiments, R1 and R1a are taken together with the carbon atom to which they are attached to form a 4-membered spirocarbocyclic ring. In some embodiments, R1 and R1a are taken together with the carbon atom to which they are attached to form a 3-membered spirocarbocyclic ring.

In some embodiments, R2 is hydrogen. In some embodiments, R2 is optionally substituted C1-6 aliphatic. In some embodiments, R2 is aliphatic C ^1-6. In some embodiments, R2 is methyl. In some embodiments, R2 is ethyl, propyl, or isopropyl. In some embodiments, R2 is methoxy or ethoxy.

In certain embodiments, an R2 is present. In certain embodiments, two R2 are present. In certain embodiments, three R2's are present.

In some embodiments, R2 is optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R2 is 3 to 6 membered monocyclic saturated carbocyclyl. In some embodiments, R2 is cyclopropyl.

In some embodiments, R2 is halogen. In some embodiments, R2 is fluorine.

In some embodiments, R2 is C1-6 aliphatic substituted with halogen. In some embodiments, R2 is -CH2F2 or -CF3. In some embodiments, R2 is C ^1-6 aliphatic substituted with hydrogen.

In some embodiments, R ³ is hydrogen. In some embodiments, R ³ is optionally substituted ^{C 1-6 aliphatic.} In some embodiments, R3 is methyl.

In some embodiments, R4 is hydrogen. In some embodiments, R4 is a natural or non-natural amino acid side chain group.

In some embodiments, R4 is an optionally substituted group selected from the group consisting of C1-6 aliphatic. In some embodiments, R4 is methyl, ethyl, isopropyl, t-butyl, -C(CH3)2OH, or -(CH2)2OH. In some embodiments, R4 is methyl. In some embodiments, R4 is isopropyl. In some embodiments, R4 is t-butyl. In some embodiments, R4 is -(CH2)mSR, -(CH2)mOH, -(CH2)mF, -(CH2)mC(O)N(R)2, or -C(O)OR, where m is 1, 2, 3, 4, 5, or 6. In some embodiments, R4 is -(CH ² ) ² SCH ³ . In some embodiments, R4 is -CH ² OH. In some embodiments, R4 is -CH ² C(O)NH or -(CH ² ) ² C(O)NH ² .

In some embodiments, m is 0, 1, 2, or 3.

In some embodiments, R4 is phenyl. In some embodiments, R4 is phenyl optionally substituted with -OH. In some embodiments, R4 is optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R4 is 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R4 is cyclopropyl. In some embodiments, R4 is cyclobutyl. In some embodiments, R4 is cyclopentyl.

In some embodiments, R4 is

In some embodiments, R4 is

In some embodiments, R4 is

In some embodiments, R4 is

In some embodiments, R4 is

In some embodiments, R4 is

In some embodiments, R4 is -(CH ² )mR7 or -CH(CH ³ )OCH ² R7, where R7 is R7 is an optionally substituted ring selected from the group consisting of phenyl, 8- to 10-membered bicyclic aryl, carbocyclyl 3-7 membered saturated or partially unsaturated monocyclic, 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, and 5 to 10 membered monocyclic or bicyclic heteroaryl having 1- 4 heteroatoms independently selected from nitrogen, oxygen or sulfur. In some embodiments, R4 is -CH ² R ⁷ , where R7 is optionally substituted phenyl. In some embodiments, R4 is -(CH ² ) ² R7, where R7 is optionally substituted phenyl. In some embodiments, R4 is -(CH ² ) ³ R7, where R7 is optionally substituted phenyl.

In some embodiments, R7 is an optionally substituted ring selected from the group consisting of an optionally substituted group selected from the group consisting of C ^1-6 aliphatic, phenyl, 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl, saturated monocyclic heterocyclyl or partially unsaturated from 3 to 7 members having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5 to 6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, saturated or partially unsaturated bicyclic carbocyclyl from 7 to 10 membered, 8 to 10 membered bicyclic aryl, saturated bicyclic heterocyclyl or 7 to 10 membered partially unsaturated having 1 to 4 heteroatoms selected from oxygen, nitrogen or sulfur, and 7 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur.

In some embodiments, R4 is -(CH ² )nSR, -(CH ² )nOH, -(CH ² )nF, -(CH ² )nC(O)N(R) ² , -C(O)OR, - (CH ² )nR7, or -CH(CHa)OCH2R7,

R7 is an optionally substituted ring selected from the group consisting of an optionally substituted group selected from the group consisting of aliphatic C ^{1 to 6,} phenyl, carbocyclyl monocyclic saturated or partially unsaturated 3 to 7 membered monocyclic heterocyclyl saturated or partially unsaturated 3 7-membered having 1-2 heteroatoms selected from oxygen, nitrogen or sulfur, 5-6 membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, 7-10 membered saturated or partially unsaturated bicyclic carbocyclyl, aryl 8 to 10 membered bicyclic, 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen or sulfur, and 7 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen , nitrogen or sulfur; and m is selected from 0, 1, 2 or 3.

In some embodiments, R7 is optionally substituted ^{C 1-6 aliphatic.} In some embodiments, R7 is isopropyl.

In some embodiments, R7 is optionally substituted phenyl. In some embodiments, R7 is phenyl substituted with one or more halogens. In some embodiments, R7 is phenyl substituted with a fluorine.

In some embodiments, R7 is optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R7 is optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur.

In some embodiments, R7 is optionally substituted 5 to 6 membered heteroaryl having 1 to 4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R7 is a 6-membered heteroaryl having one nitrogen. In some embodiments, R7 is pyridyl.

In some embodiments, R7 is optionally substituted 7 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R7 is optionally substituted 10-membered bicyclic heteroaryl having one heteroatom selected from nitrogen.

In certain embodiments, R3 and R4 are taken together with the carbon atom attached to R4 and the nitrogen atom attached to R3 to form an optionally substituted 3 to 6 membered heterocyclyl ring having 0-1 additional heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R3 and R4 together with the carbon atom attached to R4 and the nitrogen atom attached to R3 form a 5-membered monocyclic heterocycle. For example, in the compound of Example 6-012, R3 and R4 form a 5-membered monocyclic heterocycle having one nitrogen:

In some embodiments, R5 is hydrogen. In some embodiments, R5 is optionally substituted ^{C 1-6 aliphatic.} In some embodiments, R5 is methyl.

In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an optionally substituted 3 to 6 membered spiroheterocyclic ring having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a 4-membered spiroheterocyclic ring having one oxygen. For example, in the compound of Example 6-224, R4 and R5 form a 4-membered spiroheterocyclic ring having one oxygen:

In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form an optionally substituted 3 to 6 membered saturated or partially unsaturated monocyclic spirocarbocyclic ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a 3-membered saturated or partially unsaturated monocyclic spirocarbocyclic ring. In some embodiments, R4 and R5 are taken together with the carbon atom to which they are attached to form a 4-membered saturated or partially unsaturated monocyclic spirocarbocyclic ring.

In some embodiments, L is a covalent bond. In some embodiments, L is a straight or branched hydrocarbon chain, saturated or unsaturated C ^1-10 divalent, optionally substituted, in which one, two or three methylene units of L are optionally and independently replaced by -O-, -SO -, -S(O) ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC( O)-, -N(R)C(O)-, -N(R)S(O) ² -, or -S(O^N(R)-. In some embodiments, L is a saturated straight chain or C ^1-10 bivalent unsaturated, optionally substituted with one or more halogens, -CF ³ or -OH In some embodiments, L is optionally substituted with -CH ² - In some embodiments, L is -CH ² -, where - CH ² - is substituted with one or two methyl groups In some embodiments, L is -CH ² -, where -CH ² - is substituted with two methyl groups In some embodiments, L is -CH ² -, where - CH ² - is substituted with methyl.

In some embodiments, L is -CH ² CH ² - optionally substituted. In some embodiments, L is -CH ² CH ² - substituted with one or more methyl groups. In some embodiments, L is -CH ² CH ² -substituted with methyl. In some embodiments, L is -CH ² CH ² -substituted with -OH. In some embodiments, L is -CH ² CH ² - substituted with halogen. In some embodiments, L is -CH ² CH ² - substituted with fluorine.

In some embodiments, L is optionally substituted ^{-CH 2} CH ² CH ^{2 -.} In some embodiments, L is -CH ² CH ² CH ² -substituted with -OH. In some embodiments, L is -CH ² CH ² CH ² -substituted with -CH ² OH.

In some embodiments, L is a straight or branched hydrocarbon chain, saturated or unsaturated C ^1-10 divalent, optionally substituted, in which one, two or three methylene units of L are optionally and independently replaced by -Cy-. In some embodiments, one or two methylene units of L are independently replaced by -Cy- where -Cy- is 4 to 7 membered saturated or partially unsaturated monocyclic heterocyclylene having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, L is

In some embodiments, L is

In some embodiments, L is a straight or branched chain hydrocarbon, saturated or unsaturated C ^1-10 divalent, optionally substituted, in which one, two or three methylene units of L are replaced by -Cy- optionally independently - O-, -SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, - OC(O)-, -N(R)C(O)-, -N(R)SO ² -, or -SO ² N(R)-.

^{In some embodiments, L is an optionally substituted C 1-5} bivalent saturated or unsaturated straight or branched hydrocarbon chain in which one, two, or three methylene units of L are optionally and independently replaced by -Cy-, -O -, -SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC (O)-, -N(R)C(O)-, -N(R)SO ² -, or -SO ² N(R)-.

In some embodiments, L is an optionally substituted C1-4 bivalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of L are optionally and independently substituted by -Cy-, -O-, - SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O) -, -N(R)C(O)-, -N(R)SO ² -, or -SO ² N(R)-. In some embodiments, L is an optionally substituted C1-3 divalent saturated or unsaturated, straight or branched hydrocarbon chain in which one or two methylene units of L are optionally and independently replaced by -Cy-, -O-, - SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O) -, -N(R)C(O)-, -N(R)SO ² -, or -SO2N(R)-.

In some embodiments, L is a straight or branched chain hydrocarbon, saturated or unsaturated C ^2-6 bivalent, optionally substituted, in which one, two or three methylene units of L are replaced by -Cy- optionally independently - O-, -SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, - OC(O)-, -N(R)C(O)-, -N(R)SO ² -, or -SO ² N(R)-.

In some embodiments, L is a straight or branched hydrocarbon chain, saturated or unsaturated C ^2-4 bivalent, optionally substituted, in which one or two methylene units of L are optionally and independently replaced by-Cy-, -O-, -SO-, -SO ² -, -C(O)-, -C(O)N(R)-, -S-, -N(R)-, -C(O)O-, -OC(O )-, -N(R)C(O)-, -N(R)SO ² -, or -SO2N(R)-.

In some embodiments, one or two methylene units of L are replaced by -Cy-. In some embodiments, -Cy- is selected from:

In some embodiments, L is selected from:

In some embodiments, R6 is optionally substituted phenyl. In some embodiments, R6 is phenyl. In some embodiments, R6 is phenyl substituted with one or more groups selected from -OR, -NO2, -CN, -SR, -N(R)2, -C(O)R, -C(O)OR, -S (O)R, -S(O) ² R, -C(O)N(R) ² , -S(O) ² N(R) ² , -OC(O)R, -N(R)C( O)R, -N(R)C(O)OR, -N(R)SO ² R, or OC(O)N(R) ² .In some embodiments, R6 is phenyl substituted with -CN. In some embodiments, R6 is phenyl substituted with -OCF ³ .

In some embodiments, R6 is phenyl substituted with -S (O) CH ^3. In some embodiments, R6 is phenyl substituted with -S(O)CH ² CH ³ . In some embodiments, R6 is phenyl substituted with -S(O) ² CH ³ . In some embodiments, R6 is phenyl substituted with -S(O) ² CH ² CH ³ . In some embodiments, R6 is phenyl substituted with -S(O) ² CH(CH ³ ) ² . In some embodiments, R6 is phenyl substituted with -S(O) ² CH ² CH ³ . In some embodiments, R6 is phenyl substituted with -S(O) ² NH ² . In some embodiments, R6 is phenyl substituted with -NHS(O) ² CH ³ . In some embodiments, R6 is phenyl substituted with CH ² NH(CH ³ ). In some embodiments, R6 is phenyl substituted with -S(O) ² CH ³ and -CH ² N(CH ³ ) ² .

In some embodiments, R6 is phenyl substituted with one or more halogen groups. In some embodiments, R6 is phenyl substituted with one or more fluorine groups. In some embodiments, R6 is phenyl substituted with one or more chloro groups. In some embodiments, R6 is phenyl substituted with a fluorine. In some embodiments, R6 is phenyl substituted with a chlorine. In some embodiments, R6 is phenyl substituted with two fluorine groups. In some embodiments, R6 is phenyl substituted with three fluorine groups. In some embodiments, R6 is phenyl substituted with -CF ^3. In some embodiments, R6 is phenyl substituted with -CF ³ and fluorine. In some embodiments, R6 is phenyl substituted with one fluorine and one chlorine.

In some embodiments, R6 is phenyl substituted with one or more optionally substituted ^{C1-6 aliphatics.} In some embodiments, R6 is phenyl substituted with one or more methyl groups.

In some embodiments, R6 is optionally substituted 5- to 6-membered heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from oxygen or nitrogen. In some embodiments, R6 is optionally substituted 6-membered heteroaryl having 1-2 heteroatoms selected from nitrogen. In some embodiments, R6 is

In some embodiments, R6 is optionally substituted pyridyl, pyrimidinyl, or pyrazinyl. In some embodiments, R6 is pyridyl. In some embodiments, R6 is pyridyl substituted with -CN or -CF ^3. In some embodiments, R6 is halogen substituted pyridyl. In some embodiments, R6 is fluorine-substituted pyridyl. In some embodiments, R6 is pyridyl substituted with -CF ³ and fluorine. In some embodiments, R6 is

In some embodiments, R6 is pyridyl substituted with morpholinyl. In some embodiments, R6 is pyridyl substituted with piperazinyl.

In some embodiments, R6 is halogen substituted pyrimidinyl. In some embodiments, R6 is fluorine-substituted pyrimidinyl. In some embodiments, R6 is pyrimidinyl substituted with -CF ^3. In some embodiments, R6 is pyrimidinyl substituted with -NH ^2.

In some embodiments, R6 is morpholinyl-substituted pyrazinyl. In some embodiments, R6 is pyrazinyl substituted with piperazinyl. In some embodiments, R6 is pyrazinyl substituted with

In some embodiments, R6 is optionally substituted 5-membered heteroaryl having 1-3 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is 5-membered heteroaryl optionally substituted having 2 heteroatoms selected from oxygen, nitrogen or sulfur. In some embodiments, R6 is optionally substituted thiazolyl or imidazolyl.

In some embodiments, R6 is optionally substituted 7 to 10 membered bicyclic heteroaryl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 10-membered bicyclic heteroaryl having 2 heteroatoms selected from nitrogen. In some embodiments, R6 is optionally substituted 10-membered bicyclic heteroaryl having 1 heteroatom selected from nitrogen. In some embodiments, R6 is optionally substituted 9-membered bicyclic heteroaryl having 1 heteroatom selected from nitrogen.

In some embodiments, R6 is optionally substituted 7 to 10 membered saturated or partially unsaturated bicyclic heterocyclyl having 1-4 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 9-membered saturated or partially unsaturated bicyclic heterocyclyl having one heteroatom selected from sulfur.

In some embodiments, R6 is optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having 1-2 heteroatoms selected from oxygen or nitrogen. In some embodiments, R6 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having one oxygen and one nitrogen. In some embodiments, R6 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having two nitrogens. In some embodiments, R6 is optionally substituted morpholinyl. In some embodiments, R6 is optionally substituted piperazine. In some embodiments, R6 is morpholinyl substituted with one or more methyl groups. In some embodiments, R6 is optionally substituted 6-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from oxygen. In some embodiments, R6 is

In some embodiments, R6 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 2 heteroatoms selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having 2 heteroatoms selected from oxygen or nitrogen. In some embodiments, R6 is optionally substituted oxazolidinyl or dioxolanyl. In some embodiments, R6 is dioxolanyl substituted with two methyl groups.

In some embodiments, R6 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from oxygen. In some embodiments, R6 is optionally substituted 5-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from nitrogen. In some embodiments, R6 is optionally substituted pyrrolidinyl or tetrahydrofuranyl. In some embodiments, R6 is pyrrolidinyl or tetrahydrofuranyl.

In some embodiments, R6 is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from oxygen, nitrogen, or sulfur. In some embodiments, R6 is optionally substituted 4-membered saturated or partially unsaturated monocyclic heterocyclyl having one heteroatom selected from oxygen. In some embodiments, R6 is optionally substituted oxetanyl. In some embodiments, R6 is oxetanil.

In some embodiments, R6 is optionally substituted 3 to 7 membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R6 is optionally substituted 6-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R6 is optionally substituted cyclohexyl. In some embodiments, R6 is cyclohexyl. In some embodiments, R6 is cyclohexyl substituted with one or more halogen groups. In some embodiments, R6 is cyclohexyl substituted with two fluorine groups. In some embodiments, R6 is

In some embodiments, R6 is optionally substituted 5-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R6 is optionally substituted cyclopentyl. In some embodiments, R6 is cyclopentyl.

In some embodiments, R6 is optionally substituted 4-membered saturated or partially unsaturated monocyclic carbocyclyl. In some embodiments, R6 is optionally substituted cyclobutyl. In some embodiments, R6 is cyclobutyl.

In some embodiments, R6 is -OR, -NO ² , -CN, -SR, -N(R) ² , -C(O)R, -C(O)OR, -S(O)R, -S( O) ² R, -C(O)N(R) ² , -S(O) ² N(R) ² , -OC(O)R, -N(R)C(O)R, -N(R )C(O)OR, -N(R)S(O) ² R, or -OC(O)N(R) ² . In some embodiments, R6 is -OH. In some embodiments, R6 is -CN. In some embodiments, R6 is -OCF3. In some embodiments, R6 is -SOCH3. In some embodiments, R6 is -S(O)CH2CH3. In some embodiments, R6 is -S(O)2CH3. In some embodiments, R6 is -S(O) ² CH ² CH ³ . In some embodiments, R6 is -S(O) ² CH(CH ³ ) ² . In some embodiments, R6 is -S(O) ² NH ² . In some embodiments, R6 is -NHS(O) ² CH ³ . In some embodiments, R6 is -CH ² NHCH ³ ).

In some embodiments, R6 is halogen. In some embodiments, R6 is fluorine. In some embodiments, R6 is chlorine. In some embodiments, R6 is hydrogen.

In some embodiments, R6 is an optionally substituted group selected from:

In some embodiments, R6 is substituted with one or more groups selected from the group consisting of -halogen, -OR, -NO ² , -CN, -SR, -N(R) ² , -C(O)R, -C (O)OR, -S(O)R, -S(O) ² R, -C(O)N(R) ² , -S(O) ² N(R) ² , -OC(O)R, -N(R)C(O)R, -N(R)C(O)OR, -N(R)S(O) ² R, -OC(O)N(r ) ² , and aliphatic C ^{1- 6} optionally substituted with halogen. In some embodiments, R6 is substituted with one or more groups selected from the group consisting of methyl, -F, -CI, -OH, -OCH ³ , -NH ² , -NHCH ³ , -N(CH3)CH3, -CF3 , -CN, -OCF3, -S(O)2CH3, and -NHS(O)2CH3.

In some embodiments, R6 is optionally substituted ^{C1-6 aliphatic.} In some embodiments, R6 is C ^1-6 aliphatic. In some embodiments, R6 is -CF ^3.

In some embodiments, R6 is selected from:

In some embodiments, L is a covalent bond and R6 is hydrogen.

In some embodiments, L is a covalent bond and R6 is phenyl. In some embodiments, L is -CH ² - and R6 is phenyl. In some embodiments, L is a -CH ² (CH ³ )- and R6 is phenyl.

In some embodiments, L is -CH ² - and R6 is phenyl substituted with a fluorine. In some embodiments, L is -CH ² - and R6 is phenyl substituted with two fluorine groups. In some embodiments, L is -CH ² - and R6 is

In some embodiments, L is -CH ² - and R6 is

In some embodiments, L is a covalent bond and R6 is cyclohexyl. In some embodiments, L is a covalent bond and R6 is cyclopentyl. In some embodiments, L is a covalent bond and R6 is cyclobutyl. In some embodiments, L is a covalent bond and R6 is

In some embodiments, L is a covalent bond and R6 is tetrahydropyranyl. In some embodiments, L is a covalent bond and R6 is tetrahydrofuranyl. In some embodiments, L is a covalent bond and R6 is oxetanil.

In some embodiments, provided that the compounds are of formula II:

or a pharmaceutically acceptable salt thereof, wherein each of R2, R4, R5, R6 and L is as defined above and is described in classes and subclasses herein, both individually and in combination. In some embodiments, the compounds provided that they are of formula III:

or a pharmaceutically acceptable salt thereof, wherein each of R4, R5, R6 and L is as defined above and is described in classes and subclasses herein, both individually and in combination.

In some embodiments, provided that the compounds are of formula III-a:

or a pharmaceutically acceptable salt thereof, wherein each of R4, R5, R6 and L is as defined above and is described in classes and subclasses herein, both individually and in combination. In some embodiments of compounds of formula III-a, L is a covalent bond and R6 is

In some embodiments, provided that the compounds are of formula IV:

or a pharmaceutically acceptable salt thereof, wherein each of R1, R1a, Rb, Rb1, Ra, R4, R5, and R6 is as defined above and is described in classes and subclasses herein, both individually and in combination . In some embodiments, each Ra is independently -hydrogen, -halogen, -OR, -NO ² , -CN, -SR, -N(R)2, -C(O)R, -C(O)OR, -S (O)R, -S(O)2R, -C(O)N(R)2, -S(O)2N(R)2, -OC(O)R, -N(R)C(O) R, -N(R)C(O)OR, -N(R)S(O) ² R, or -OC(O)N(R) ² . In some embodiments, each Ra is independently hydrogen, methyl, -F, -Cl, -CF ³ , -CN, -OCF ³ , or -S(O) ² CH ³ . In some embodiments, Ra is independently fluorine or chlorine.

In some embodiments, Rb and Rb1 are hydrogen. In some embodiments, Rb and Rb1 are methyl. In some embodiments, Rb is methyl and Rb1 is hydrogen. In some embodiments of compounds of formula IV, R6 is fluorine and one Ra is fluorine. In some embodiments of compounds of formula IV, R6 is fluorine and two Ra's are fluorine.

In some embodiments, the compounds provided that they are of formula V:

or a pharmaceutically acceptable salt thereof, wherein each of Rb, Rb1, Ra and R6 is as defined above and is described in classes and subclasses herein, both individually and in combination. In some embodiments of compounds of formula V, R6 is -S(O)2CH3 and Ra is -CH2N(CH3)2.

In some embodiments, the compounds provided they are of formula V-a and V-b:

or a pharmaceutically acceptable salt thereof, wherein each of Ra and R6 is as defined above and is described in classes and subclasses herein, both individually and in combination.

In some embodiments, provided that the compounds are of formula VI-a, VI-b, VI-c, VI-d, VI-e or VI-f:

or a pharmaceutically acceptable salt thereof, wherein each of n, Ra and R6 is as defined above and is described in classes and subclasses herein, both individually and in combination. In some embodiments of compounds of formula VI-af, n is 1,2 and 3. In some embodiments of compounds of formula VI-af, R6 is -F, -CF3, -Cn, -N(CH3)2, -NH (CH3) or -NH2 and Ra is hydrogen. In some embodiments of compounds of formula VI-a-f, R6 is hydrogen and Ra is hydrogen.

In some embodiments, provided that the compounds are of formula VII-a, VII-b, or VII-c:

or a pharmaceutically acceptable salt thereof, wherein each of n, Ra and R6 is as defined above and is described in classes and subclasses herein, both individually and in combination. In some embodiments of compounds of formula VII-a-c, n is 0, 1, 2, and 3.

In some embodiments, provided that the compounds are of formula VIII-a, VIII-b, or VIII-c:

or a pharmaceutically acceptable salt thereof, wherein each of R2, R6 and L is as defined above and is described in classes and subclasses herein, both individually and in combination.

In some embodiments, provided that the compounds are of formula IX-a or IX-b:

or a pharmaceutically acceptable salt thereof, wherein R is hydrogen or methyl and L is as defined above and described in classes and subclasses herein. In some embodiments, provided that the compounds are of formula IX-a or IX-b and L is selected from:

General Methods for Providing the Present Compounds

The compounds of the invention are synthesized by an appropriate combination of generally well known synthetic methods. Useful techniques for synthesizing the compounds of the invention are readily apparent and accessible to those skilled in the relevant art. The discussion below is offered to illustrate some of the various methods available for use in assembling the compounds of the invention. However, the discussion is not intended to define the scope of the reactions or reaction sequences that are useful in preparing the compounds of the present invention.

In certain embodiments, the present compounds are generally prepared according to Scheme A set forth below:

wherein R1, R1a, R2, R3, R4, R5, R6, and L are each as defined and described in classes and subclasses herein, and PG and LG are described below.

The "LG" group in Scheme A is a suitable leaving group, ie, groups that are subject to nucleophilic displacement. A "suitable leaving group" is a chemical group that is readily displaced by a desired incoming chemical moiety, such as an amine. Suitable leaving groups are well known in the art, eg, see "Advanced Organic Chemistry", Jerry March, 5th Ed., pp. 351-357, John Wiley and Sons, N.Y. Such leaving groups include, but are not limited to, halogen, alkoxy, sulfonyloxy, optionally substituted alkylsulfonyloxy, optionally substituted alkenylsulfonyloxy, optionally substituted arylsulfonyloxy, acyl, and diazonium moieties. Examples of suitable leaving groups include chlorine, iodine, bromine, fluorine, acetoxy, methoxy, methanesulfonyloxy (mesyloxy), tosyloxy, trifliloxy, nitro-phenylsulfonyloxy (nosyloxy), and bromo-phenylsulfonyloxy (brosiloxy).

The "PG" groups in Scheme A are a suitable protecting group, as defined above and described herein. One of skill in the art will be familiar with a variety of protecting groups and protecting group strategies that can be employed. Suitable hydroxyl and amino protecting groups are well known in the art and include those described in detail in Protecting Groups in Organic Synthesis, T. W. Greene and P. G. M. Wuts, 3rd edition, John Wiley & Sons, 1999.

In Step S-1, amino acid A is coupled under suitable conditions with compound B to form compound C. In some embodiments, Step S-1 employs a suitable base. Such suitable bases and suitable conditions are known in the art and may vary according to LG's choice. In some embodiments, a suitable base is an inorganic base. In some embodiments, a suitable base is K ² CO ³ .

One skilled in the art will appreciate that a variety of suitable LG leaving groups of compound B can be used to facilitate the reaction described in Step S-1, and all such suitable leaving groups are contemplated by the present invention. In some embodiments, LG is halogen. In some embodiments, LG is chlorine. In some embodiments, LG is trichloroacetimidate.

Step S-1 may optionally employ a suitable solvent. Such suitable solvents include, for example, polar aprotic solvents (ie, THF, DMF, dioxane, acetonitrile, and combinations thereof).

In Step S-2, compound C is deprotected under suitable conditions as described in Greene and Wuts (supra) to form amine D. These suitable conditions are known in the art and may vary depending on the choice of protecting group. In some embodiments, PG is a Boc group and suitable conditions comprise a suitable acid. In certain embodiments, a suitable acid is an inorganic acid or a Lewis acid. In some embodiments, the acid is HCl.

In Step S-3, amine D is coupled under suitable conditions with carboxylic acid E to form a compound of formula I. Step S-3 may employ peptide coupling reagents. In some embodiments, a peptide coupling reagent is selected from FDPP, PFPOH, BOP-CI, Ed C, EDCA, DCC, DIC, HOBt, HOAt, HBTU, HATU, HCTU, TBTU, PyBOP, or a combination thereof. In some embodiments, suitable conditions comprise a suitable coupling reagent selected from EDCI/HOBt, PyBOP, HATU, or BEM (Carpino, LAJ Am. Chem. Soc. 1993, 115, 4397. Carpino, LA; EI-Faham, AJ Am. Chem. Soc. 1995, 117, 5401. Li, P., Xu, JCJ Pept. Res. 2001, 58, 129.) in the presence of a base familiar to one skilled in the art and in an appropriate solvent. In certain embodiments, a suitable base is an amine base. In some embodiments, an amine base is DIPEA. In some embodiments, suitable solvents for Step S-3 include, for example, polar aprotic solvents (ie, THF, DMF, dioxane, acetonitrile, and combinations thereof).

An exemplary synthesis of useful intermediates such as carboxylic acid E is depicted in Scheme B. Additional syntheses are depicted in the following Examples.

In Step S-4, the acid F is esterified under suitable conditions to form the ester G, where Re is a suitable group to form a carboxylic ester. In some embodiments, Re is C ^1-6 aliphatic. Suitable reagents for the esterification of the acid F include alcohols. Step S-4 may employ a suitable acid. In certain embodiments, a suitable acid is an inorganic acid or a Lewis acid. In some embodiments, the acid is H ² SO ⁴ .

In Step S-5, the ester G undergoes formylation to form salicylaldehyde H. Suitable conditions for the ortho-formulation of phenols are known in the art. In some embodiments, suitable conditions comprise MgCl ² , an amine base, and paraformaldehyde. In some embodiments, an amine base is Et ³ N. Step S-5 may optionally employ a suitable solvent. Suitable solvents for use in Step S-5 include polar aprotic solvents (ie, THF, methyl-THF, dioxane, acetonitrile, and combinations thereof).

In Step S-6, salicylaldehyde H is reacted to form compound J. In some embodiments, XJ is -OTf. Suitable conditions for the introduction of a triflate group are known in the art. In some embodiments, Step S-6 includes a base. In some embodiments, a base is an amine base. In certain embodiments, an amine base is pyridine, DMAP, or a combination thereof.

In Step S-7, compound J is borylated under suitable conditions to provide boronic ester K. Suitable conditions for the borylation of triflates are known in the art. In some embodiments, suitable conditions comprise bis(pinacolato)diboron, a base, and a palladium catalyst. In some embodiments, a base is potassium acetate. In some embodiments, a palladium catalyst is [1,1-bis(diphenylphosphino)ferrocene]dichloropalladium(II). Step S-7 may optionally employ a suitable solvent. Suitable solvents for use in Step S-7 include aprotic solvents (ie, THF, methyl-THF, dioxane, acetonitrile, toluene, and combinations thereof).

It will be appreciated that groups other than triflate are suitable for compound J and the borylation chemistry. For example, compound J may have a halogen (eg chlorine, bromine, iodine) instead of an -OTf group. Suitable conditions for installing such a halogen group from compound H or other precursors are known in the art, as are conditions for subsequent borylation. See, for example, WO 2015013318 A1 as well as the following Examples.

In Step S-8, the boronic ester K is cyclized under suitable conditions to provide oxaborol L. In some embodiments, suitable conditions include a reducing agent. Suitable reducing agents include metal hydrides, for example borohydrides. In some embodiments, a reducing agent is sodium borohydride. Step S-8 optionally employs a suitable acid after reduction. In certain embodiments, a suitable acid is an inorganic acid or a Lewis acid. In some embodiments, the acid is HCl. Step S-8 may optionally employ a suitable solvent. Suitable solvents for use in Step S-8 include, by way of non-limiting example, THF, dioxane, methanol, ethanol, and combinations thereof.

In Step S-9, the oxaborol L is hydrolyzed to provide carboxylic acid E. Suitable conditions for ester hydrolysis are known in the art and include a base or acid catalyzed reaction of an ester with water. Suitable bases include alkali hydroxides. In some embodiments, a suitable base is NaOH. In some embodiments, Step S-9 comprises an aqueous NaOH solution.

In certain embodiments, each of the aforementioned synthetic steps may be performed sequentially with isolation of each intermediate performed after each step. Alternatively, each of steps S-1, S-2, S-3, S-4, S-5, S-6, S-7, S-8 and S-9 as shown in Schemes A and B above, can be performed in a manner in which isolation of one or more intermediates is not performed. Furthermore, it will be readily apparent to one of ordinary skill in the art that additional steps may be taken to achieve particular protecting group and/or deprotection strategies.

In certain embodiments, all of the steps in the aforementioned synthesis can be performed to prepare the desired final product. In other embodiments, two, three, four, five, or more sequential steps may be performed to prepare a desired intermediate or final product.

The skilled artisan will appreciate that certain starting materials depicted in Schemes A and B can be readily interchanged with other starting materials or reagents to provide additional compounds of formula I. Such substitutions could be made with routine experimentation. For example, the amide nitrogen of the coupling product of amine D and carboxylic acid E can be modified to provide R3 groups other than hydrogen. Furthermore, alkyl groups can be installed at the R1 position through Grignard chemistry in intermediate aldehydes. Post-oxidation to the ketone followed by a similar introduction of an R1a group can also be performed.

Compounds for use

In certain embodiments, the compounds of the present invention are for use in medicine. In some embodiments, the compounds of the present invention are useful in the treatment of parasitic infections. The term "parasitic infection" includes diseases or disorders involving parasites. In some embodiments, a "parasitic infection" includes diseases or disorders involving parasites such as Trypanosoma cruzi, Trypanosoma congolense, Trypanosoma vivax, and Trypanosoma evansi.

In some embodiments, the compounds of the present invention are useful as therapeutics against trypanosomatids. In some embodiments, the parasites that can be treated with compounds of the present invention are Trypanosoma cruzi, Trypanosoma congolense, Trypanosoma vivax, and Trypanosoma evansi.

The term "subject" as used herein refers to a mammal to which a pharmaceutical composition is administered. Exemplary subjects include humans, as well as veterinary and laboratory animals such as horses, pigs, cattle, dogs, cats, rabbits, rats, mice, and aquatic mammals.

In certain embodiments, the present invention provides a compound for use in treating a T. congolense- mediated disease or disorder in a subject comprising administering to a subject a provided compound. In some embodiments, the disease is trypanosomiasis. In some embodiments, the disease is African animal trypanosomiasis (AAT).

In certain embodiments, the present invention provides a compound for use in treating a T. vivix- mediated disease or disorder in a subject comprising administering to a subject a provided compound. In some embodiments, the disease is trypanosomiasis. In some embodiments, the disease is African animal trypanosomiasis (AAT).

In some embodiments, the present invention provides a compound for use in treating AAT comprising administering a provided compound to a subject suffering from AAT. In some embodiments, the subject suffering from AAT is a mammal. In some embodiments, the subject suffering from AAT is a species of cattle. In some embodiments, the subject suffering from AAT is a cow.

In certain embodiments, the present invention provides a compound for use in treating a T. cruzi- mediated disease or disorder in a subject comprising administering to a subject a provided compound. In some embodiments, the disease is Chagas disease. In some embodiments, the present invention provides a compound for use in treating Chagas disease comprising administering a provided compound to a subject suffering from Chagas disease. In some embodiments, the subject suffering from Chagas disease is a mammal. In some embodiments, the subject suffering from Chagas disease is a human. In some embodiments, the subject suffering from Chagas disease is a dog.

In some embodiments, the half maximum inhibitory concentration (IC ⁵⁰ ) of the compound against a parasite is less than 1 pM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 500 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 100 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 10 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 1 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 0.1 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 0.01 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is less than 0.001 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is from 0.01 nM to 1 uM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is from 0.01 nM to 10 uM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is from 0.1 nM to 10 uM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is from 0.1 nM to 1 uM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is from 0.1 nM to 100 nM. In some embodiments, the IC ⁵⁰ of the compound against a parasite is from 0.1 nM to 10 nM.

The term "treatment" (also "treating" or "treating"), as used herein, refers to any administration of a substance (for example, a pharmaceutical composition) that relieves, ameliorates, revives, inhibits, or delays the partial or complete onset of, reduces the severity, and/or reduces the incidence of one or more symptoms, features, and/or causes of a particular disease, disorder, and/or condition. Such treatment may be of a subject showing no signs of the relevant disease, disorder and/or condition and/or of a subject exhibiting only early signs of the disease, disorder and/or condition. Alternatively or additionally, such treatment may be of a subject exhibiting one or more established signs of the relevant disease, disorder and/or condition. In some embodiments, the treatment may be of a subject diagnosed as suffering from the relevant disease, disorder and/or condition. In some embodiments, the treatment may be of a subject known to have one or more susceptibility factors that are statistically correlated with an increased risk of developing the relevant disease, disorder and/or condition.

Approved more than four decades ago, the two drugs available to treat Chagas, benzinidazole and nifurtimox, require long-term therapy (60-90 days), have serious safety problems (20-30% of side effects result in discontinuation of treatment), have variable efficacy in chronic infections and Chagasic cardiomyopathy, are contraindicated in pregnancy and have associated drug resistance. In some embodiments, the compounds are used in the treatment of a subject previously treated for a parasitic infection. In some embodiments, the compounds are used in the treatment of a subject previously treated with benzinidazole and/or nifurtimox. In some embodiments, the compounds are used in the treatment of a parasitic infection refractory to treatment with benzinidazole and/or nifurtimox.

Pharmaceutical compositions

In another aspect, the present disclosure provides pharmaceutical compositions comprising a compound of formula I or a compound of formula I in combination with a pharmaceutically acceptable excipient (eg, carrier).

Pharmaceutical compositions include optical isomers, diastereomers, or pharmaceutically acceptable salts of the inhibitors described herein. The compound of formula I included in the pharmaceutical composition may be covalently linked to a carrier moiety, as described above. Alternatively, the compound of formula I included in the pharmaceutical composition is not covalently bound to a structural unit of the carrier.

A "pharmaceutically acceptable carrier", as used herein, refers to pharmaceutical excipients, eg, physiologically acceptable pharmaceutically acceptable organic or inorganic carrier substances suitable for enteral or parenteral application that do not react detrimentally with the active agent. Suitable pharmaceutically acceptable carriers include water, saline solutions (such as Ringer's solution), alcohols, oils, gelatins, and carbohydrates such as lactose, amylose, or starch, fatty acid esters, hydroxymethylcellulose, and polyvinylpyrrolidine. Such preparations can be sterilized and, if desired, mixed with auxiliary agents such as lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, regulators, colorants and/or aromatic substances and the like that do not react in a similar way. deleterious manner with the compounds of the invention.

The compounds of the invention may be administered alone or may be co-administered to the subject. Co-administration is intended to include simultaneous or sequential administration of the compounds individually or in combination (more than one compound). The preparations can also be combined, when desired, with other active substances (eg to reduce metabolic degradation).

Combinations

The compounds of the invention can also be used in combination with additional therapeutic agents. Therefore, the invention provides, in a further aspect, a combination comprising a compound described herein or a pharmaceutically acceptable salt thereof together with at least one therapeutic agent. additional. In an exemplary embodiment, the additional therapeutic agent is a compound of the invention. In an exemplary embodiment, the additional therapeutic agent includes a boron atom.

When a compound of the invention is used in combination with a second therapeutic agent active against the same disease state, the dose of each compound may differ from that used when the compound is used alone. Those skilled in the art will readily appreciate appropriate doses. It will be appreciated that the amount of a compound of the invention required for use in treatment will vary with the nature of the condition being treated and the age and condition of the patient, and will ultimately be at the discretion of the physician or veterinarian. attendee.

formulations

The compounds of the present invention can be prepared and administered in a wide variety of oral, parenteral, and topical dosage forms. Thus, the compounds of the present invention can be administered by injection (eg, intravenous, intramuscular, intracutaneous, subcutaneous, intraduodenal, or intraperitoneal). Additionally, the compounds described herein can be administered by inhalation, eg, intranasally. Furthermore, the compounds of the present invention can be administered transdermally. It is also envisioned that multiple routes of administration (eg, intramuscular, oral, transdermal) may be used to administer the compounds of the invention. Accordingly, the present invention also provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier or excipient and one or more compounds of the invention.

For preparing pharmaceutical compositions from the compounds of the present invention, pharmaceutically acceptable carriers may be solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances that can also act as diluents, flavoring agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid in admixture with the finely divided active component. In tablets, the active component is mixed with the carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired.

Powders and tablets preferably contain 5% to 70% of the active compound. Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting point wax, cocoa butter, and the like. The term "preparation" is intended to include the formulation of the active compound with encapsulating material as a carrier which provides a capsule in which the active component, with or without other carriers, is surrounded by, and thus associated with, a carrier. Similarly, stamps and pads are included. Tablets, powders, capsules, pills, cachets, and lozenges can be used as solid dosage forms suitable for oral administration.

For the preparation of suppositories, a low-melting wax, such as a mixture of fatty acid glycerides or cocoa butter, is first melted, and the active component is homogeneously dispersed therein, as by stirring. The molten homogeneous mixture is then poured into molds of convenient size, allowed to cool and thereby solidifies.

Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water/propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.

When parenteral application is needed or desired, particularly suitable admixtures for the compounds of the invention are sterile injectable solutions, preferably oily or aqueous solutions, as well as suspensions, emulsions or implants, including suppositories. In some embodiments, vehicles suitable for parenteral administration will be selected for human administration. In some embodiments, vehicles suitable for parenteral administration will be selected for veterinary administration. In particular, vehicles for parenteral administration include aqueous dextrose solutions, saline, pure water, ethanol, glycerol, glycerol formal, polyethylene glycol, propylene glycol, peanut oil, sesame oil, polyoxyethylene block polymers, pyrrolidine, N-methyl pyrrolidine and the like. Ampoules are convenient unit doses. The compounds of the invention can also be incorporated into liposomes or administered by transdermal pumps or patches. Pharmaceutical mixtures suitable for use in the present invention include those described, for example, in Pharmaceutical Sciences (17th edition, Mack Pub. Co., Easton, PA) and WO 96/05309.

Aqueous solutions suitable for oral use can be prepared by dissolving the active component in water and adding suitable colorants, flavors, stabilizers, and thickening agents as desired. Aqueous suspensions suitable for oral use can be prepared by dispersing the finely divided active component in water with viscous material, such as natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to be converted, shortly before use, to liquid form preparations for oral administration. Such liquid forms include solutions, suspensions, and emulsions. These preparations may contain, in addition to the active component, colorants, flavors, stabilizers, regulators, artificial and natural sweeteners, dispersants, thickeners, solubilizing agents, and the like.

The pharmaceutical preparation is preferably in unit dosage form. In such form, the preparation is subdivided into unit doses containing appropriate quantities of the active component. The unit dosage form may be a packaged preparation, the package containing discrete amounts of preparation, such as packaged tablets, capsules, and powders in vials or ampoules. Furthermore, the unit dosage form may be a capsule, tablet, cachet or lozenge itself, or it may be the appropriate number of any of these in packaged form.

The amount of active component in a unit dose preparation can be varied or adjusted from 0.1 mg to 10000 mg, more typically 1.0 mg to 1000 mg, more typically 10 mg to 500 mg, depending on the particular application and the potency of the component. active. If desired, the composition may also contain other compatible therapeutic agents.

Some compounds may have limited solubility in water and therefore may require a suitable surfactant or other co-solvent in the composition. Such co-solvents include: Polysorbate 20, 60 and 80; Pluronic F-68, F-84 and P-103; cyclodextrin; and polyoxyl 35 castor oil. Such co-solvents are typically employed at a level between about 0.01% and about 2% by weight.

Viscosity greater than that of plain aqueous solutions may be desirable to decrease variability in dispensing of formulations, decrease physical separation of components of a formulation suspension or emulsion, and/or otherwise improve formulation. Such viscosity-increasing agents include, for example, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, carboxymethylcellulose, hydroxypropylcellulose, chondroitin sulfate and its salts, hyaluronic acid and its salts, and combinations of the foregoing. Such agents are typically employed at a level between about 0.01% and about 2% by weight.

The compositions of the present invention may additionally include components to provide sustained release and/or comfort. Such components include high molecular weight anionic mucomimetic polymers, gelling polysaccharides, and finely divided drug carrier substrates. These components are discussed in greater detail in US Patent No. 4,911,920; 5,403,841; 5,212,162; and 4,861,760.

For administration to non-human animals, the composition containing the therapeutic compound may be added to the animal's feed or drinking water. Furthermore, it will be convenient to formulate animal feed and drinking water products so that the animal ingests an appropriate amount of the compound in its diet. Furthermore, it will be convenient to present the compound in a composition as a premix for addition to feed or drinking water. The composition can also be formulated as a food or drink supplement for humans.

effective dose

Pharmaceutical compositions provided by the present invention include compositions in which the active ingredient is contained in a therapeutically effective amount, that is, in an amount effective to achieve its intended purpose. The actual effective amount for a particular application will depend, among other things, on the condition being treated. For example, when administered to treat a parasitic infection, such compositions will contain an amount of active ingredient effective to achieve the desired result.

The dose and frequency (single or multiple doses) of the compound administered may vary depending on a variety of factors, including the route of administration; size, age, sex, health, body weight, body mass index, and diet of the recipient; nature and extent of symptoms of the disease being treated; presence of other diseases or other health-related problems; type of concurrent treatment; and complications of any disease or treatment regimen. Other regimens or therapeutic agents may be used in conjunction with the compounds of the invention and their uses.

For any compound described herein, the therapeutically effective amount can be initially determined from cell culture assays. Target concentrations will be those concentrations of active compound(s) that are capable of killing parasites and/or controlling their growth or reproduction as measured, for example, using the methods described.

Therapeutically effective amounts for use in humans can be determined from animal models. For example, a human dose can be formulated to achieve a concentration found to be effective in animals. The dose in humans can be adjusted by monitoring kinase inhibition and adjusting the dose up or down, as described above. Therapeutically effective amounts for use in animals (eg, cattle) can be determined from animal models (eg, mouse models).

Doses can be varied depending on the requirements of the patient and the compound being used. The dose administered to a patient, in the context of the present invention, should be sufficient to achieve a beneficial therapeutic response in the patient over time. The size of the dose will also be determined by the existence, nature and extent of any adverse side effects. Generally, treatment is started with smaller doses, which are less than the optimal dose of the compound. Thereafter, the dose is increased by small increments until the optimum effect under the circumstances is reached. In some embodiments, the dosage range is from 0.001% to 10% w/v. In some embodiments, the dosage range is from 0.1% to 5% w/v.

Dosage amounts and intervals can be individually adjusted to provide effective levels of administered compound for the particular clinical indication being treated. This will provide a therapeutic regimen commensurate with the severity of the individual's disease state.

examples

The following examples are intended to illustrate certain embodiments of the invention. In order to provide a complete description of how the compounds of the present invention are made, the Examples section that follows includes compounds that fall within the scope of the claims and also compounds that fall outside the scope of the claims.

It will be appreciated that when an Example refers to another Example with reference to "Example I-XX", the reference is to the synthesis of the respective Compound 6-XX, or the relevant part of the synthesis.

Example A-1: Preparation of Acid-04

To a solution of 1 (1.65 kg, 10.8 mol) in EtOH (6.50 L) was added concentrated HCl. H ² SO ⁴ (326 g, 3.25 mol). The reaction mixture was heated at 105°C for 24h. TLC showed that 1 was completely consumed. The mixture was cooled to 15°C and concentrated to give the crude product. The residue was poured into 2M NaHCO ³ (aqueous, 3 L) and the solid was filtered. The filtrate was concentrated to give 2 (1.75 kg, 90%) as a brown solid. 1H NMR (400 MHz, CDCh) 7.41 (d, J =7.9 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 6.94 (d, J = 7.9 Hz, 1H), 4.58 (br s, 1H ), 4.37 (q, J = 7.4 Hz, 2H), 2.46 (s, 3H), 1.40 (t, J = 7.1 Hz, 3H).

To a solution of 2 (800 g, 4.44 mol) in THF (6.50 L) was added MgCh (634 g, 6.66 mol, 273 mL), TEA (1.80 kg, 17.8 mol), and (HCHO)n (600 g, 6.66 mole). The mixture was immediately heated at 90°C for 14h. TLC showed that 2 was completely consumed. The reaction mixture was cooled to 15°C, ice H ² O (3 L) was added and HCl 12 M (1.5 L) was added slowly. The mixture was stirred for half an hour and then extracted with EtOAc (2 L). The combined organic layer was washed with saturated NaHCO ³ solution until neutral, dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 3 (880 g, crude) as a brown oil. 1H NMR (400 MHz, CDCh) 8 11.40 (s, 1H), 9.93 (s, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 4.40 (q , J = 7.4 Hz, 2H), 2.44 (s, 3H), 1.41 (t, J = 7.1 Hz, 3H).

To a solution of 3 (900 g, 4.32 mol) in DCM (7.56 L) was added pyridine (1.02 kg, 12.9 mol) and DMAP (27 g, 221 mmol) respectively. The mixture was cooled to 0°C and Tf ² O (1.60 kg, 5.66 mol) was added dropwise. The reaction mixture was warmed to 15°C and stirred for 1h. TLC showed that 3 was completely consumed. The mixture was quenched with water (7.65 L) and then extracted with DCM (7.65 L x 2). The combined organic layer was washed with water (2 L), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 4 (685 g, 47%) as a pale yellow oil. 1H NMR (400 MHz, CDCla) 10.27 (s, 1H), 7.99 (d, J = 8.0 Hz, 1H), 7.91-7.87 (m, 1H), 4.43 (q, J = 7.0 Hz, 2H), 2.64 ( s, 3H), 1.43 (t, J = 7.3 Hz, 3H).

To a solution of 4 (1.00 kg, 2.94 mol), bis(pinacolato)diboron (1.12 kg, 4.41 mol) and KOAc (573 g, 5.84 mol) in 1,4-dioxane (6.50 L) was added Pd(dppf) Ch^CH ² Ch (150 g, 184 mmol). The mixture was heated at 85°C for 15 h under N ² atmosphere. TLC showed that 4 was completely consumed. The mixture was cooled to 15°C, filtered and concentrated to give the crude product. The residue was purified by column chromatography (SiO ² , petroleum ether/ethyl acetate = 40/1 to 4:1) to give 5 (942 g, crude) as a yellow oil.

To a solution of 5 (1.20 kg, 3.77 mol) in MeOH (300 mL) and THF (6.00 L) was added NaBH4 (80 g, 2.11 mol) in portions at 0°C. Then the reaction mixture was stirred at 15°C for 1h. HPLC showed that 5 was completely consumed. The reaction solution was adjusted to pH=4 with 2M HCl, and then the organic layer was removed in vacuo. The mixture was filtered. The cake was washed with petroleum ether (5L) and dried in vacuo to give 6 (665g, 80%) as a white solid. 1H NMR (400 MHz, DMSO-d6) 9.18 (s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 5.00 (s, 2H), 4.30 ( q, J = 7.0 Hz, 2H), 2.68 (s, 3H), 1.33 (t, J = 7.0 Hz, 3H).

To a mixture of 6 (867 g, 3.94 mol) in H ² O (5.00 L), NaOH (394 g, 9.85 mol) was added in one portion. The solution was heated at 40°C for 3 hours. HPLC showed that 6 was completely consumed. This batch was treated together with the other batches and acidified with 2M HCl to pH = 2. The solid was filtered and washed with H ² O (10 L). The cake was dried to give Acid-04 (2.00 kg, 87%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 9.13 (br s, 1H), 7.89 (d, J = 8.0 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 2.68 (s, 3H).

Example A-2: Preparation of Acid-05

To a solution of 1 (100 g, 465 mmol) in MeOH (1 L) was added concentrated ^{H 2} SO ^{4 .} (20ml). The solution was heated at 80°C for 16h. The solvent was removed under reduced pressure and the residue was slowly poured into water (100 ml). The aqueous layer was extracted with EtOAc (200 mL x 3). The combined organic layers were washed with aqueous NaHCO ³ solution and brine, dried over Na ² SO ⁴ and concentrated under reduced pressure to give crude 2 (102 g) as a yellow oil. 1H NMR (400 MHz, CDCh) 8.18 (d, J = 1.2 Hz, 1H), 7.85 (d, J = 6.0, 1.76 Hz, 1H), 7.28 (d, J = 8.0 Hz, 1H), 3.90 (s, 3H), 2.44 (s, 3H).

To a solution of LiTMP (35.46 g, 251 mmol) in anhydrous THF (200 mL) was added n-BuLi (2.5 M, 100 mL, 251 mmol) dropwise at -10°C under N ² . After cooling to -60°C, a solution of 2 (50.0 g, 218 mmol) in anhydrous THF (50 mL) was added dropwise under N ² and the reaction mixture was stirred for another 30 min at -60°C. c. To the above mixture I ² (166.2 g, 654.8 mmol) was added in one portion at -60°C. The resulting solution was warmed at 0°C for one hour. The reaction mixture was quenched by saturated ^{aqueous NH 4} Cl solution, and the aqueous phase was extracted with DCM (100 mL x 3). The combined organic phase was washed with saturated aqueous Na ² S ² O ³ solution (100 mL x 3), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (petroleum ether/EtOAc = 20/1) to give 3 (20 g, 26%) as a yellow oil. 1H NMR (400 MHz, CDCla) 7.45 (d, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 3.96 (s, 3H), 2.59 (s, 3H).

A mixture of 3 (20.0 g, 56.3 mmol), NBS (10.0 g, 56.3 mmol), and BPO (1.36 g, 5.63 mmol) in CCl ⁴ (200 mL) was heated at 80 °C for 12 h under N ^{2 atmosphere.} . Then NBS (10.0 g, 56.3 mmol) and BPO (1.36 g, 5.63 mmol) were added again. After heating at 80°C for a further 6h, the solvent was removed under reduced pressure to give crude 4, which was used in the next step without further purification.

A mixture of 4 (24.0 g, 55.3 mmol) and AcOK (10.86 g, 110.6 mmol) in DMF (250 mL) was heated at 80 °C for 4 h under N ² atmosphere. The solvent was removed under reduced pressure. The residue was diluted with water (100 ml), and the aqueous layer was extracted with MTBE (100 ml x 3). The combined organic layers were washed with brine (500 mL), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography (SiO ² , petroleum ether/EtOAc = 20/1 to 5:1) to give 5 (7.00 g, 31%) as a yellow solid.

1H NMR (400 MHz, CDCh) 7.51 (d, J = 8.0 Hz, 1H), 7.44 (d, J = 8.0 Hz, 1H), 5.24 (s, 2H), 3.96 (s, 3H), 2.19 (s , 3H).

To a mixture of 5 (1.65 g, 4.00 mmol), trifluoro(vinyl)-^4-borane potassium salt (696 mg, 5.20 mmol) and Cs ² CO ³ (2.61 g, 8.00 mmol) in 1,4-dioxane ( 30 mL) and water (0.4 mL) Pd(dppf)Ch^CH ² Ch (326 mg, 0.400 mmol) was added. The reaction mixture was heated at 100°C for 18 h under N ² atmosphere. The solvent was removed under reduced pressure. The crude was purified by preparative TLC with petroleum ether:EtOAc = 10:1 as eluent to obtain 6 (0.60 g, 48%) as a yellow oil. 1H NMR (400 MHz, CDCh) 7.61 (d, J =8.4 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 6.93 (q, J =10.8 Hz, J = 6.8 Hz, 1H), 5.49 (d, J = 10.0 Hz, 1H), 5.27 (m, 1H), 5.23 (s, 2H), 3.84 (s, 3H), 2.17 (s, 3H).

To a mixture of 6 (0.63 g, 2.0 mmol), AcOK (395 mg, 4.00 mmol) and BPD (1.0 g, 4.0 mmol) in dioxane (12 mL) was added Pd(dppf)Ch^CH ² Ch (164 mg , 0.2mmol). The reaction mixture was stirred at 100°C for 14 h under N ² atmosphere. The solvent was removed under reduced pressure. The crude was purified by preparative TLC (SiO ² , petroleum ether/EtOAc = 10/1) to give 7 (0.40 g, 55.2%) as a pale yellow oil. 1H NMR (400 MHz, CDCh) 7.87 (d, J = 7.6 Hz, 1H), 7.44 (d, J =11.2 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 5.36 (d, J = 11.2 Hz, 1H), 5.30 (d, J = 17.6 Hz, 1H), 5.19 (s, 2H), 3.85 (s, 3H), 2.09 (s, 3H), 1.36 (s, 12H).

To a solution of 7 (0.40 g, 1.1 mmol) in MeOH (10 mL) and water (0.3 mL) was added NaOH (133 mg, 3.33 mmol). The solution was stirred at 50°C for 14h. The solvent was removed under reduced pressure. The residue was diluted with water (5 mL) and adjusted to pH = 2 with 2M HCl. After filtration, ⁸ (160 mg, 71%) was obtained as a yellow solid. 1H NMR (400 MHz, CDCh) 8.98 (s, 1H), 7.77 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 (t, J = ^6.8 Hz, 1H), 5.70 (d, J = 12 Hz, 1H), 5.42 (d, J =11.6 Hz, 1H), 5.00 (s, 1H).

A mixture of ⁸ (160 mg, 0.73 mmol) and 10% Pd/C (0.2 g) in MeOH (80 mL) was stirred at 20°C for 14 h under H ² (14 psi). After filtration, the filtrate was concentrated under reduced pressure to give Acid-05 (150 mg, 99%) as a white solid. MS (ESI): calculated mass. for C ¹⁰ H ¹¹ BO ⁴ 206.00, m/z found 205.2 [MH]-.1H NMR (400 MHz, DMSO-cfe) 12.74 (s, 1H), 9.06 (s, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 3.12 (m, 2H), 1.12 (t, J = 7.6 Hz, 1H).

Example A-3: Preparation of Acid-06

To a mixture of 1 (obtained in Reference Example 2; 1.65 g, 4.00 mmol), cyclopropylboronic acid (446 mg, 5.20 mmol) and Cs ² CO ³ (2.61 g, ⁸ mmol) in 1,4-dioxane (30 ml) and water (3 ml) Pd (dppf)ChCH ² Ch (326 mg, 0.40 mmol) was added. The reaction mixture was heated at 100°C for 18 h under N ² atmosphere. The solvent was removed under reduced pressure. The crude mixture was purified by preparative TLC with PE:EtOAc = 10:1 as eluent to obtain 2 (0.55 g, 43%) as a yellow oil. 1H NMR (400 MHz, CDCla) 7.47 (d, J = 8.0 Hz, 1H), 7.29 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 3.92 (s, 1H), 5.27 (m, 3H), 2.16 (s, 3H), 2.03-1.99 (m, 1H), 1.09 (q, J =5.6 Hz, J = 8.4 Hz, 1H), 0.49 (q, J = 5.2 Hz, J = 5.6 Hz, 1 HOUR).

To a mixture of 2 (0.50 g, 1.5 mmol), KOAc (300 mg, 3 mmol) and 3 (1.38 g, 6.10 mmol) in dioxane ⁽⁸ mL) was added Pd (dppf) Cl ² + CH ² Ch (500 mg, 0.60mmol). The reaction mixture was stirred at 110°C for 14 h under N ² atmosphere. The solvent was removed under reduced pressure. The crude mixture was purified by preparative TLC (SiO ² , PE/EA = 20/1) to give 4 (0.35 g, 64%) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.54 (d, J = 7.6 Hz, 1H), 7.25 (d, J = 7.2 Hz, 1H), 5.18 (s, 2H), 3.88 (s, 3H), 3.79 (s, 4H), 2.40 (m, 1H), 2.07 (s, 3H), 1.26 (s, ^6H), 0.88 (s, 2H), 0.50 (t, J = 4.4 Hz, 2H).

To a solution of 4 (0.32 g, 0.90 mmol) in MeOH (12 mL) and water (4 mL) was added NaOH (106 mg, 2.67 mmol). The solution was stirred at 80°C for 14h. The solvent was removed under reduced pressure. The residue was diluted with water (5 mL) and adjusted to pH = 2 with 2M HCl. After filtration, Acid-06 (170 mg, ⁸ %) was obtained as a pale yellow solid. MS (ESI): mass calculated for C ¹¹ H ¹¹ BO ⁴ 218.01, m/z found 219.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ⁶ ) 12.82 (s, 1H), 8.93 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 2.27 (m, 1H), 0.89 (d, J = 7.2 Hz, 2H), 0.70 (d, J = 8.4 Hz, 2H).

Example A-4: Preparation of Acid-07

To a solution of 1 (obtained in Reference Example 1; 50 mg, 157 umol) in THF (4 mL) was added MeMgBr (21 mg, 172 umol) at -78°C. The mixture was stirred at -78°C for 1h. The reaction mixture was quenched with saturated NH ⁴ Cl solution (20 mL) at 15°C and then extracted with EtOAc (5 mL x 2). The combined organic layers were washed with saturated brine (5 mL x 2), dried over ^{anhydrous Na 2} SO ⁴ , filtered, and concentrated under reduced pressure to give a residue. The residue was dissolved in DCM (5 mL) and then washed with 1M HCl. The organic layer was washed with saturated brine (5 mL), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated under reduced pressure. to give a residue. The residue was purified by preparative TLC (PE/EtOAc = 5/1) to give 2 (20 mg, 54%) as a yellow solid. 1 H NMR (400 MHz, CDCh) 8.01 (d, J = 8.0 Hz, 1 H ), 7.16 (d, J = 8.0 Hz, 1 H), 5.30 (q, J = 6.4 Hz, 1 H), 4.38 (q, J = 7.2 Hz, 2 H), 2.80 (s, 3 H), 1.52 (d, J = 6.4 Hz, 3 H), 1.41 (t, J = 7.2 Hz, 3 H).

A mixture of 2 (160 mg, 683 umol) and NaOH (82 mg, 2.0 mmol) in MeOH (10 mL) and water (10 mL) was degassed and purged with N ² 3 times. The mixture was stirred at 50°C for 4 h under N ² atmosphere. The solvent was removed under reduced pressure. The solution was adjusted with 1M HCl to pH=2-3. A white solid then precipitated and was filtered to give Acid-07 (100 mg, 71%) as a white solid. MS (ESI): mass calculated for C ¹⁰ H ¹¹ BO ⁴ 206.00, m/z found 207.1 [M+H]+. 1H NMR (400 MHz, DMSO-d ⁶ ) 12.74 (s, 1H), 9.04 (s, 1H), 7.89 (d, J = 8.0 Hz, 1 H), 7.27 (d, J = 8.0 Hz, 1 H) , 5.22-5.17 (m, 1H), 2.67 (s, 3H), 1.40 (d, J = ^6.8 Hz, 3H).

Example A-5: Preparation of Acid-08

This compound was prepared from compound 1 obtained in Example A-2 and trifluoro(2-propenyl)-^4-borane potassium salt in a similar manner to Example A -2.1H NMR (400 MHz, DMSO-cfe ) 12.90 (s, 1H), 9.26 (s, ^1H), 7.56 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.99 (s, 2H), 3.58 ( t, J = 7.2 Hz, 1H), 1.35 (d, J = 6.8 Hz, 6H).

Example A-6: Preparation of Acid-09

A mixture of 1 (obtained in Reference Example 2, 200 mg, 484 umol), allyl(tributyl)stannane (160 mg, 0.484 mmol), Pd(PPh ³⁾⁴ (56 mg, 48 umol) in dioxane (5 ml) was degassed and purged with N ² 3 times, and then the mixture was stirred at 80°C for ¹² h under N ² atmosphere. The solvent was removed under reduced pressure. The residue was purified by preparative TLC (PE/EtOAc = 5/1) to give 2 (80 mg, 50%) as a yellow liquid. 1H NMR (400 MHz, CDCla) 7.78 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 6.00-5.91 (m, 1H), 5.24 (s, 2H), 5.08- 4.99 (m, 2H), 3.98 (d, J = 6.0 Hz, 2H), 3.90 (s, 3H), 2.19 (s, 3H). Acid-09 was obtained in a similar manner to Example A-2. MS (ESI): mass calculated for C ¹¹ H ¹³ BO ⁴ 220.03, m/z found 221 [M+H]+.

Example A-7: Preparation of Acid-10

A mixture of 1 (obtained in Reference Example 2, 300 mg, 726 umol), Cul (276 mg, 1.5 mmol), 2 (139 mg, 726 umol), and HMPA (651 mg, 4 mmol) in DmF( 5 mL) was stirred at 80°C for 12 h under N ² atmosphere. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC (TFA condition) to give 3 (30mg, 12%) as a white solid. 1H NMR (400 MHz, CDCla) 7.62 (d, J =7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 5.28 (s, 2H), 3.93 (s, 3H), 2.19 (s, 3H).

A mixture of 3 (100 mg, 281 umol), Pd(dppf)Cl ² (82 mg, 0.11 mmol) and 2-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5, 5-dimethyl-1,3,2-dioxaborinane (127 mg, 0.563 mmol) and AcOK (55 mg, 0.56 mmol) in dioxane (5 mL) were stirred at 100°C for 12 h under N ² atmosphere. The mixture was purified by preparative TLC (petroleum ether/EtOAc = 5/1) to give crude 4 (35mg) as a yellow solid. 1H NMR (400 MHz, CDCh) 7.80 (d, J = 6.4 Hz, 1H), 7.60 (d, J = 7.2 Hz, 1H), 5.25 (s, 2H), 3.92 (s, 3H), 3.80 (s, 4H), 2.11 (s, 3H), 1.18 (s, 6H).

To a mixture of 4 (900 mg, 2.00 mmol) in MeOH (9 mL) and H ² O (10 mL) was added NaOH (371 mg, 9.00 mmol). The mixture was stirred at 50°C for 12h. The organic solvent was removed under reduced pressure and the aqueous layer was adjusted to pH = 2-3 with 1M HCl. The solid was collected after filtration. The crude material was initially purified by preparative TLC (petroleum ether/EtOAc = 1/1) then purified by preparative HPLC (TFA condition) to give the Acid-10 mixture (150mg) as a white solid. MS (ESI): calculated mass. for C ⁹ H ⁶ BF ³ O ⁴ 245.95, found m/z 247 [M+H]+.

Example A-8: Preparation of Acid-11

To a solution of 1 (15 g, 55 mmol) in DCM (100 mL) was added DAST (89.0 g, 553 mmol) dropwise at 0°C. The mixture was stirred at 0°C for 16h. The reaction mixture was poured into ^{saturated NaHCO 3} (200 mL) slowly at 0°C and then extracted with DCM (100 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 2 (11 g, 68% yield) as pale yellow oil. 1H NMR (400 MHz, CDCh) 7.53 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 35.6 Hz, 1H), 4.38 (q, J = 8.0 Hz, 6.0 Hz, 2H), 2.49 (s, 3H), 1.38 (t, J =7.2 Hz, 3H).

A mixture of 2 (9.0 g, 31 mmol), NBS (6.0 g, 34 mmol), and BPO (744 mg, 3.00 mmol) was degassed in CCl ⁴ (100 mL) and purged with N ² 3 times. The reaction mixture was stirred at 80°C for 16 h under N ² atmosphere. The solvent was removed under reduced pressure to give 3 (11 g, crude) as a pale yellow solid which was used in the next step without further purification.

A mixture of 3 (11 g, crude) and AcOK (3.0 g, 33 mmol) in DMF (30 mL) was stirred at 60 °C for 2 h under N ² atmosphere. The reaction mixture was diluted with H ² O (100 ml) and then extracted with MTBE (100 ml x 2). The combined organic layers were washed with 100 mL brine (50 mL x 2), dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (petroleum ether/EtOAc = 10/1) to give 4 (4.0 g, 39%) as pale yellow oil. 1H NMR (400 MHz, CDCh) 7.65 (d, J = 8.0 Hz, 1H), 7.57 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 54 Hz, 1H), 5.25 (s, 2H) , 4.40 (q, J = 7.2 Hz, 2.8 Hz, 2H), 2.18 (s, 3H), 1.39 (t, J = 7.2 Hz, 3H).

A mixture of 4 (50.0 mg, 142 umol), BPD (145 mg, 0.569 mmol), AcOK (56.0 mg, 0.569 mmol), and Pd(dppf)Ch (21 mg, 0.028 mmol) in dioxane (2 mL) was degassed. and purged with N ² 3 times. The mixture was stirred at 90°C for 12 h under N ² atmosphere. The reaction mixture was directly purified by preparative TLC (petroleum ether/EtOAc = 5/1) to give 5 (5.0 mg, 8.8% yield) as a white solid. 1H NMR (400 MHz, CDCl ³ ) 7.96 (d, J = 8.0 Hz, 1H), 7.72-7.37 (m, 2H), 5.23 (s, 2H), 4.39 (d, J =7.2 Hz, 2H), 2.12 (s, 3H), 1.42 (s, 12H).

A mixture of 5 (240 mg, 0.603 mmol) and NaOH (96 mg, 2.0 mmol) in MeOH (2 mL) and H ² O (2 mL) was stirred at 50 °C for 12 h under N ² atmosphere. The reaction mixture was concentrated under reduced pressure. The mixture was adjusted to pH=4 with 1M HCl. The mixture was concentrated under reduced pressure to give Acid-11 (100mg) as a white solid. Ms (ESI): mass calculated for C ⁹ H ⁷ BF ² O ⁴ 227.96, m/z found 229 [M+H]+.

Example A-9: Preparation of Acid-12

Step 1: To a stirring solution of compound 1 (10 g, 60.2 mmol) in DCM (100 mL), TICI ⁴ (1 M solution in DCM, 150 mL, 150 mmol) was added dropwise at room temperature (room temperature ). Br ² (3.09 mL, 60.2 mmol) was then added to the reaction mixture at room temperature. The reaction mixture was stirred at room temperature for 15 min. The progress of the reaction was monitored by TLC. TLC showed the formation of two nearby polar points with complete consumption of compound 1. The reaction was quenched with ice water and extracted into petroleum ether (3 x 500 mL). The combined organic layers were washed with water, brine, and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to give crude material. The crude compound was purified by column chromatography on silica gel (100-200 mesh, 100% petroleum ether) and 2.5 g of compound 2 (2.5 g, 12%), 8 g of compound 2A and 5.4 g of a mixture of compound 2 and compound 2A was isolated.

Step 2: To a stirring solution of compound 2 (2.4 g, 9.836 mmol) in DMF (48 mL) was added K ² CO ³ (2.0 g, 14.75 mmol) at room temperature and stirred at room temperature for 30 min. Mel (0.735 mL, 11.8 mmol) was then added at room temperature and stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. TLC showed the formation of a nonpolar spot with complete consumption of compound 2. The reaction mixture was quenched with ice water and extracted into EtOAc (2 x 200 mL). The combined organic layers were washed with water, brine, and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to give crude material. The crude compound was purified by column chromatography on silica gel (100-200 mesh, 2% EtOAc in petroleum ether) to give compound 3 (2.5 g, 99%).

Step 3: To a stirring solution of compound 3 (2.5 g, 9.689 mmol) in CCl ⁴ (25 mL) was added AIBN (317 mg, 1.937 mmol) and NBS (2.06 g, 11.627 mmol) at room temperature. The reaction mixture was heated at reflux for 18h. The reaction mixture was concentrated under reduced pressure to give a crude residue. The residue was diluted with water and EtOAC. The organic layer was separated, washed with water, brine and dried over Na ² SO ⁴ . Solvent was removed under reduced pressure to obtain crude material. The crude compound was purified by column chromatography (normal phase, 3% EtOAc:petroleum ether) to obtain compound 4 (1.5 g, 46%) as a yellow syrup.

Step 4: To a stirring solution of compound 4 (1.3 g, 3.869 mmol) in CH ³ CN (26 mL) was added KOAc (1.13 g, II.607 mmol) at room temperature. The reaction mixture was stirred at reflux temperature for 18h. TLC-monitored reaction progress and TLC showed the formation of a polar spot with complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to give a crude residue. The crude residue was diluted with water and EtOAc. The organic layer was separated, washed with water, brine and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to obtain compound 5 (1.2 g, 98%) as an off-white solid.

Step 5: To a stirred solution of compound 5 (17 g, 5.379 mmol) in 1,4-dioxane (20 vol) was added KOAc (1.58 g, 16.13 mmol) and bis-(neopentylglycolate)diborane (243 g), 10,759 mmol) at room temperature. The reaction mixture was degassed and flushed with argon for 20 min. Pd(dppf)Ch was then added. DCM (0.219 g, 0268 mmol) at room temperature. The reaction mixture was heated at 80°C for 3h. The progress of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature and filtered through a pad of celite. The filtrate was concentrated under reduced pressure to give a crude material. The crude compound was purified by silica gel column chromatography (100-200 mesh, 15%-20% EtOAc:petroleum ether) to yield compound 6 (1.5 g, 80%) as a yellow syrup.

Step 6: To a stirring solution of compound 6 (1.5 g, semi-pure, 4.285 mmol) in MeOH (10 vol) was added 1N NaOH (0.514 g, 12.857 mmol) at 0°C. The reaction mixture was stirred at room temperature for 5h. The progress of the reaction was monitored by TLC and TLC showed the formation of a polar spot with complete consumption of starting material. The reaction mixture was acidified with 2N HCl to pH 3.0 and stirring was continued at room temperature for 30 min. The reaction mixture was diluted with water and extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine solution and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to give the crude compound. The crude compound was purified by reverse phase HPLC to obtain compound 7 (400 mg, 42%) as a pale yellow solid.

Step 7: To a stirring solution of compound 7 (400 mg, 1.8 mmol) in H ² O (20 vol) was added NaOH (216 mg, 5.404 mmol) at 0°C. The reaction mixture was left at room temperature for 5 h. The progress of the reaction was monitored by TLC and TLC showed the formation of a polar spot with complete consumption of starting material. The reaction mixture was acidified with 2N HCl to pH 4.0 at 0°C and extracted with EtOAc (2x 100 mL). The combined organic layers were washed with brine and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to give compound 8 (303 mg, 80%) as a white solid. 1H NMR (300 MHz, DMSo-d6): 812.6 (s, 1H), 9.34 (s, 1H), 7.76 (d, 1H), 7.10 (d, 1H), 5.02 (s, 2H), 4.0 (s, 3H); LC-MS: m/z 209.01 [M+H]+.

Example A-10: Preparation of Acid-13

Acid-13 was prepared from iodoethane with compound 2 followed by the same method as the synthesis of Acid-12.

Step 1: To a stirring solution of compound 2 (3 g, 12.3 mmol) in DMF (30 mL) was added K ² CO ³ (2.54 g, 18.4 mmol) at room temperature and stirred for 30 min. Etl (2.92 mL, 36.9 mmol) was then added at room temperature and the reaction mixture was stirred at room temperature for 16 h. The progress of the reaction was monitored by TLC. TLC showed the formation of a non-polar spot with complete consumption of starting material. The reaction mixture was quenched with ice water and extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with water, brine, and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to give a crude material. The crude compound was purified by column chromatography on silica gel (100-200 mesh: 2-4% EtOAc in petroleum ether) to give compound 3 (2.2 g, 66%) as a colorless liquid.

1H NMR (300 MHz, DMSO-d6): 812.6 (s, 1H), 9.25 (s, 1H), 7.72 (d, 1H), 7.10 (d, 1H), 5.02 (s, 2H), 4.32 (qt, 2H), 1.28 (t, 3H); LC-MS: m/z 223.33 [M+H]+.

Example A-11: Preparation of Acid-14

This compound was prepared from 5-hydroxy-2-methylbenzoic acid in a similar manner to Example A-1. 1H NMR (400 MHz, DMSO-cfe) 8.22 (s, 1H), 7.29 (s, 1H), 4.96 (s, 2H), 2.54 (s, 3H).

Example B-1: Preparation of 4-fluorobenzyl-L-valinate

To a solution of N-BOC-(S)-valine (500.00 g, 2.30 mol, 1.00 eq) and 4-fluorobenzyl alcohol (290 g, 2.30 mol, 248.10 mL) in dry DCM (6.0 L) was added DCC (854 g, 4.14 mol, 838 mL) and DMAP (39.36 g, 322.19 mmol). The reaction mixture was stirred at 25°C for 15h. The mixture was filtered and washed with DCM (2L) and concentrated to give the crude product. The residue was purified by column chromatography (SiO ² , petroleum ether/ethyl acetate=50/1 to 10:1) to give 4-fluorobenzyl(tert-butoxycarbonyl)-L-valinate (708 g, 95% yield ) as a white solid. 1H NMR (400 MHz CDCh) 67.35 (dd, J = 8.2, 5.5, Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H), 5.19-5.08 (m, 2H), 5.01 (d, J =8.4 Hz, 1H), 4.25 (dd, J = 8.4, 4.4, Hz, 1H), 2.13 (dd, J = 6.2, 11.9 Hz, 1H), 1.44 (s, 9H), 0.93 (d, J =7.1 Hz,

3H), 0.84 (d, J = 7.1 Hz, 3H).

The mixture of 4-fluorobenzyl(tert-butoxycarbonyl)-L-valinate (1.06 kg, 3.26 mol) in EtOAc/HCl (6.0 L) was stirred at 25°C for 14 h. The solvent was removed under reduced pressure to give 4-fluorobenzyl L-valinate hydrochloride (780g, 91%). It was obtained as a white solid. 1H NMR (400 MHz CDCla) 68.90 (br s, 3H), 7.37 (dd, J = 8.2, 5.5,Hz, 2H), 7.03 (t, J = 8.4 Hz, 2H), 5.29-5.10 (m, 2H) , 3.95 (br s, 1H), 2.44 (dd, J =11.0, 6.6 Hz, 1H), 1.08 (dd, J =10.1, 7.1 Hz, 6H).

Example 1. 2,6-dimethylphenyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-001)

To a solution of compound 1 (1.22 g, 10.0 mmol), compound 2 (1.98 g, 10.5 mmol), and DMAP (122 mg, 1.00 mmol) in dichloromethane (50 mL), DCC (2.26 g, 11.0 mmol) was slowly added. at 0°C. The mixture was stirred at 10°C overnight. The reaction mixture was concentrated and purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to give compound 3 (2.0 g, 68% yield) as a white solid, which it was used for the following steps and confirmed in the final stage.

To a solution of compound 3 (1.0 g, 3.4 mmol) in ethyl acetate (20 mL), a solution of HCl in ethyl acetate ⁽⁴ M, 20 mL) was added slowly at 0°C. The mixture was stirred at 10°C for 1 hour. TLC (PE:EA=10:1) showed that the starting material was completely consumed. The reaction mixture was concentrated to dryness to give compound 4 (750 mg, 95% yield) as a white solid.

To a solution of Acid-01 (ACS Med. Chem. Lett., 2010, 1(4), 165-169, 178 mg, 1.00 mmol), compound 4 (230 mg, 1.00 mmol), EDC (384 mg, 2.00 mmol) and HOBt (270 mg, 2.00 mmol) in DMF (5 mL) DIPEA (387 mg, 3.00 mmol) was added. The reaction mixture was stirred at 10°C overnight, then concentrated and purified by preparative HPLC to give 6-001 (270 mg, 76% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 69.31 (s, 1H), 9.02 (d, J = 6.62 Hz, 1H), 8.30 (s, 1H), 8.00 (dd, J =7.94 Hz, 1.32 Hz, 1H) , 7.51 (d, J =8.38 Hz, 1H), 7.13-6.99 (m, 3H), 5.04 (s, 2H), 4.74 (t, J = 6.84 Hz, 1H), 2.10 (s, 6H), 1.63 ( d, J = 7.06 Hz, 3H);

ESI-MS: m/z 354 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 2. tert-Butyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-002)

This compound was prepared from (S)-alanine tert-butyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 89.30 (s, 1H), 8.68 (t, J = 6.2 Hz, 1H), 8.22 (s, 1H), 7.96-7.92 (m, 2H), 5.01 (s, 2H), 4.30 (quint., J = 6.1 Hz, 1H), 1.37 (s , 9H), 1.35 (d, J = 6.1 Hz, 3H); ESI-MS: m/z 364 [M+OAc]-; HPLC purity: 100% (220nm), 100% (254nm).

Example 3. (1-Hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valine (6-003)

Compound 6-003 was prepared from Acid-04 and tert-butyl L-valinate in a similar manner to the last step of Example 1 followed by addition of HCl and purification by preparative HPLC (column: Luna C8 100 x 30 mm; liquid phase: TFA-ACN at 0.1%; B%: 10%-35%, 12 min). 1H NMR (400 MHz, DMSO-d6) 812.53 (s, 1H), 9.00 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 7.43 - 7.13 (m, 2H), 4.95 (s, 2H ), 4.27 (dd, J = 8.2 Hz, 6.4 Hz, 1H), 2.46 (s, 3H), 2.22 - 1.99 (m, 1H), 0.94 (t, J = 6.8 Hz, 6H); ESI-MS: m/z 292 [M+H]+; HPLC purity: 99.18% (220nm), 100% (254nm).

Example 4. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)glycinate (6-004)

This compound was prepared from glycine benzyl ester and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 89.32 (s, 1H), 8.99 (t, J = 6.0 Hz, 1H) , 8.23 (s, 1H), 7.93 (dd, J = 7.9, 1.32 Hz, 1H), 7.49 (d, J = 7.94 Hz, 1H), 7.41-7.21 (m, 5H), 5.14 (s, 2H), 5.03 (s, 2H), 4.06 (d, J = 5.7 Hz, 2H); ESI-MS: m/z 326 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 5. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-005)

This compound was prepared from (S)-valine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 89.31 (br s, 1H), 8.66 ( d, J = 7.5 Hz, 1H), 8.23 (s, 1H), 7.95 (dd, J = 7.9, 1.76 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 7.38-7.31 (m, 4H ), 5.24-5.09 (m, 2H), 5.04 (s, 2H), 4.33 (t, J = 7.5 Hz, 1H), 2.29 2.11 (m, 1H), 0.95 (dd, J = 18.96, 6.62 Hz, 6H ). ESI-MS: m/z 368 [M+H]+; HPLC purity: 98.3% (220nm), 100% (254nm).

Example 6. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-leuccinate (6-006)

This compound was prepared from (S)-leucine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.32 (s, 1H), 8.79 (d , J = 7.94 Hz, 1H), 8.23 (s, 1H), 7.93 (d, J = 7.9 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.38-7.25 (m, 5H), 5.12 (s, 2H), 5.03 (s, 2H), 4.52 (dd, J = 6.8, 3.31 Hz, 1H), 1.90-1.42 (m, 3H), 0.90 (d, J = 6.4 Hz, 3H), 0.87 (d, J = 6.4 Hz, 3H), 6.39 Hz, 6H); ESI-MS: m/z 382 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 7. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-serinate (6-007)

This compound was prepared from (S)-serine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.34 (s, 1H), 8.67 (d , 1H), 7.87 (s, 1H), 7.80 (d, 2H), 7.41-7.26 (m, 4H), 5.14 (s, 2H), 5.03 (s, 2H), 4.58 (m, 1H), 3.88- 3.77 (m, 2H); ESI-MS: m/z 356 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 8. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-methioninate (6-008)

This compound was prepared from (S)-methionine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.32 (br s, 1H) 8.84 (d , J = 7.5 Hz, 1H), 8.23 (s, 1H), 7.94 (d, J = 7.9 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.38-7.22 (m, 5H), 5.14 (d, J = 4.0 Hz, 2H), 5.03 (s, 2H), 4.68-4.51 (m, 1H), 2.68-2.51 (m, 2H), 2.12-2.04 (m, 2H), 2.01 (s, 3H ); ESI-MS: m/z 400 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm). Example 9. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-phenylalaninate (6-009)

This compound was prepared from (S)-phenylalanine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.31 (s, 1H), 8.92 (d , J = 8.0 Hz, 1H), 8.17 (s, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H,), 7.36-7.14 (m, 9H), 5.11 (d, J = 4.41 Hz, 2H), 5.02 (s, 2H), 4.65-4.77 (m, 1H), 3.22-3.07 (m, 2H);

ESI-MS m/z 416 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 10. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-asparaginate (6-010)

This compound was prepared from (S)-glutamine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-de) 8.90 (d, J = 7.06 Hz, 1H ) 8.25 (s, 1H), 7.96 (dd, J = 8.0, 1.76 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H), 7.36-7.31 (m, 5H), 6.82(brs, 1H), 5.19-5.10(m, 2H), 5.04 (s, 2H), 4.47(brs, 1H), 2.28-2.19 (m, 2H), 2.16-2.04 (m, 1H), 2.03-1.90 (m, 1H); ESI-MS m/z 397 [M+H]+; HPLC purity: 99.39% (220nm), 100% (254nm).

Example 11. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-glutaminate (6-011)

This compound was prepared from (S)-glutamine benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-de) 8.82 (d, J = 7.5 Hz, 1H ), 8.21 (s, 1H), 7.91 (dd, J = 8.2, 1.54 Hz, 1H), 7.49 (d, J = 7.9 Hz, 1H), 7.42 (br s, 1H), 7.38-7.23 (m, 5H ), 6.97 (br s, 1H), 5.13 (s, 2H), 5.04 (s, 2H), 4.78-4.90 (m, 1H), 2.58-2.81 (m, 2H); ESI-MS m/z 383 [M+H]; HPLC purity: 98.69% (220nm), 97.33% (254nm).

Example 12. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-prolinate (6-012)

This compound was prepared from (S)-proline benzyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-de) 7.92 (s, 1H), 7.66-7.53 (m, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.41-7.13 (m, 5H), 5.16 (s, 2H), 5.05-4.95 (m, 2H), 4.55 (dd, J = 7.9 , 4.41 Hz, 1H), 3.61-3.47 (m, 2H), 2.36-2.24 (m, 1H), 1.99-1.76 (m, 3H); ESI-MS: m/z 366[M+H]; HPLC purity: 100% (220nm), 100% (254nm).

Example 13. Benzyl 2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-2-methylpropanoate (6-013)

This compound was prepared from benzyl 2-amino-2-methylpropanoate and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-de) 9.31 (s, 1H), 8.71 (s, 1H), 8.20 (s, 1H), 7.90 (dd, J = 7.94, 1.32 Hz, 1H), 7.47 (d, J =7.94 Hz, 1H), 7.34-7.18 (m, 5H), 5.04 (d, J =13.67 Hz, 4H), 1.48 (s, 6H); ESI-MS m/z 354 [M+H]; HPLC purity: 99.78% (220nm), 100% (254nm).

Example 14. 2,6-Dimethylbenzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-014)

A mixture of compound 5 (775 mg, 5.00 mmol), compound 2 (1.00 g, 5.25 mmol) and K2CO3 (1.38 g, 10.0 mmol) in DMF (20 mL) was stirred at 10 °C overnight. The reaction mixture was concentrated in vacuo and purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to give compound 6 (1.3 g, 89% yield) as a white solid. . Similar to the last step of Example 1, 6-014 was obtained in two more steps from compound 6. 1H NMR (400 MHz, DMSO-cfe) 59.30 (s, 1H), 8.82 (d, J = 6.6 Hz, 1H ), 8.21 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.47 (d, J = 7.9 Hz, 1H), 7.15-7.07 (m, 1H), 7.01 (d, J = 7.5 Hz , 2H), 5.21-5.08 (m, 2H), 5.05-4.96 (m, 2H), 4.43 (q, J =7.2 Hz, 1H), 2.29 (s, 6H), 1.37 (d, J =7.1 Hz, 3H); ESI-MS: m/z 390 [M+Na]+; HPLC purity: 98.83% (220nm), 100% (254nm).

Example 15 2-phenylpropan-2-yl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-015)

To a solution of compound 7 (1.36 g, 10 mmol) in dry THF (20 mL), NaH (60% in mineral oil, 240 mg, 10 mmol) was added slowly at 0°C. The mixture was stirred at 10°C for 0.5 hour. CChCN (1.43 g, 10 mmol) was then added dropwise at 0°C, the resulting mixture was stirred at 10°C for 1 hour. The organic solvent was removed in vacuo and the residue was suspended in hexane (20 mL) and MeOH (1 mL). The solid was filtered off and washed with hexane (3 x 5 mL). The filtrate was concentrated to dryness to give compound 8 (2.4 g, 86% yield) as a yellow oil.

A solution of compound 8 (837 mg, 3 mmol) and compound 9 (622 mg, 2 mmol) in DCM (30 mL) was stirred at 10°C for 1 hour. TLC (PE:EA = 5:1) indicated that the starting material was completely consumed. The suspension was filtered. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (PE:EA = 10:1 to 5:1) to give compound 10 (850 mg, 98% yield) as yellow oil. .

Piperidine (85 mg, 1 mmol) was slowly added to a solution of compound 10 (429 mg, 1 mmol) in DMF (5 mL), the reaction mixture was stirred at 10°C for 1 hour. TLC (PE:EA = 5:1) indicated that the starting material was completely consumed. The suspension was filtered. The filtrate was concentrated to dryness in vacuo to give compound 11 (200 mg, 97% yield) as a yellow oil.

To a solution of Acid-1 (178 mg, 1 mmol), compound 11 (207 mg, 1 mmol), EDCI (384 mg, 2 mmol) and HOBT (270 mg, 2 mmol) in DMF (5 mL) was added DIPEA (387mg, 3mmol). The mixture was stirred at 10°C overnight and then purified by preparative HPLC to give 6-015 (50mg, 14% yield) as a white solid. 1H NMR (400 MHz, DMSO-C6) 59.28 (s, 1H), 8.73 (d, J =7.1 Hz, 1H), 8.24 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.39-7.34 (m, 2H), 7.29 (t, J =7.5 Hz, 2H), 7.24-7.18 (m, 1H), 5.03 (s, 2H), 4.46 ( q, J = 7.3 Hz, 1H,), 1.69 (d, J = 8.4 Hz, 6H), 1.42 (d, J =7.50 Hz, 3H). ESI-MS m/z 390 [M Na]+; HPLC purity: 98.55% (220nm), 98.90% (254nm).

Example 16. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-016)

This compound was prepared from (S)-alanine methyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.30 (s, 1H), 8.80 ( d, J = 6.8 Hz, 1H), 8.22 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 5.01 (s, 2H), 4.45 ( quint., J = 7.2 Hz, 1H), 3.61 (s, 3H), 1.37 (d, J = 7.2 Hz, 3H); ESI-MS m/z 264 [M+H] ; HPLC purity: 100% (220nm), 100% (254nm).

Example 17. Benzyl (S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3,3-dimethylbutanoate (6-017)

This compound was prepared from benzyl (S)-2-amino-3,3-dimethylbutanoate and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.34 (s , 1H), 8.44 (d, J = 8.4 Hz, 1H), 7.83 (s, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.40-7.29 (m, 5H), 5.18 (d, J = 12.5 Hz, 1H), 5.11 (d, J = 12.5 Hz, 1H), 5.03 (s, 2H), 4.44 (d, J = 8.4 Hz, 1H), 1.02 (s, 9H); ESI-MS m/z 382 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 18. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-D-phenylalaninate (6-018)

This compound was prepared from benzyl (S)-phenylalanine methyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6) 9.31 (s, 1H), 8.87 (d, J = 7.9 Hz, 1H), 8.18 (s, 1H), 7.89 (dd, J = 7.9, 1.32 Hz, 1H), 7.48 (d, J = 7.9 Hz, 1H), 7.25-7.32 (m, 4H), 7.16-7.22 (m, 1H), 5.03 (s, 2H), 4.68 (ddd, J = 9.7, 7.7, 5.5 Hz, 1H), 3.64 (s, 3H), 3.05-3.22 (m, 2H) ; ESI-MS m/z 340 [M+H]+; HPLC purity: 96.83% (220nm), 95.71% (254nm).

Example 19 (R)-1-Phenylethyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-019)

This compound was prepared from (R)-1-phenylethane-1-ol, compound 2 and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.28 (s 1H), 8.80 (d, J = 6.4 Hz, 1H), 8.22 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 7.6 Hz, 1H), 7.37-7.30 (m, 5H) , 5.80 (m, 1H), 5.02 (s, 2H), 4.48 (t, J = 6.8 Hz, 1H), 1.43-1.41 (m, 6H); ESI-MS m/z 376 [M+Na]+; HPLC purity: 99.63% (220nm), 100% (254nm).

Example 20. (R)-1-Phenylethyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-020)

This compound was prepared from (R)-1-phenylethane-1-ol, N-BOC-(S)-valine and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-da) 9.28 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.20 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 -7.26 (m, 5H), 5.83 (m, 1H), 5.01 (s, 2H), 4.29 (t, J = 8.0 Hz, 1H), 2.23-2.18 (m, 3H), 0.98 (d, J = 7.2 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); ESI-MS m/z 404 [M+Na]+; HPLC purity: 99.80% (220nm), 100% (254nm).

Example 21 (R)-1-phenylethyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-phenylalaninate (6-021)

This compound was prepared from (R)-1-phenylethane-1-ol, N-BOC-(S)-phenylalanine, and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.28 (s, 1H), 8.86 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.85 (d, J = 8.0 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.31-7.24 (m, 10H), 5.75 (m, 1H), 5.00 (s, 2H), 4.68 (m, 1H), 3.14 (d, J = 7.6 Hz, 3H), 1.30 (d, J = 6.8 Hz , 3H); ESI-MS m/z 452 [M+Na]+; HPLC purity: 99.22% (220nm), 98.01% (254nm).

Example 22 (S)-1-phenylethyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-022)

This compound was prepared from (S)-1-phenylethane-1-ol, N-BOC-(S)-alanine, and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.28 (s, 1H), 8.78 (d, J = 6.8 Hz, 1H), 8.22 (s, 1H), 7.93 (m, 1H), 7.47 (d, J =8.4 Hz, 1H), 7.32-7.26 (m, 5H), 5.79 (m, 1H), 5.02 (s, 2H), 4.49 (t, J = 6.8 Hz, 1H), 1.45 (d, J = 6.8 Hz, 3H), 1.36 (d, J = 7.6 Hz, 3H);

ESI-MS m/z 376 [M+Na]+; HPLC purity: 94.63% (220nm), 91.44% (254nm).

Example 23 (S)-1-Phenylethyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-023)

This compound was prepared from (S)-1-phenylethane-1-ol, N-BOC-(S)-valine and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.33 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 8.25 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.40 -7.30 (m, 5H), 5.87 (m, 1H), 5.06 (s, 2H), 4.35 (m, 1H), 2.21 (m, 1H), 1.51 (d, J = 6.8 Hz, 3H), 0.91 0.89 (m, 6H); ESI-MS m/z 404 [M+Na]+; HPLC purity: 98.86% (220nm), 98.19% (254nm).

Example 24 (S)-1-phenylethyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-phenylalaninate (6-024)

This compound was prepared from (S)-1-phenylethane-1-ol, N-BOC-(S)-phenylalanine, and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.02 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 8.17 (s, 1H), 7.85 (d, J = 7.6 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.31 -7.17 (m, 10H), 5.85 (m, 1H), 5.02 (s, 2H), 4.76 (m, 1H), 3.18 (m, 1H), 3.17 (m, 1H), 1.49 (d, J = 6.8 Hz, 3H); ESI-MS m/z 452 [M+Na]+; HPLC purity: 98.92% (220nm), 98.77% (254nm).

Example 25. Methyl (R)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-4-phenylbutanoate (6-025)

A solution of compound 12 (1 g, 5.6 mmol) in MeOH (40 mL) was bubbled with HCl gas at 0°C for 30 min. The mixture was then concentrated to dryness at 35°C. The residue was washed with MTBE and filtered to give compound 13 (0.80 g, 73%) which was used in the next step without further purification.

Compound 6-025 was prepared from 13 and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6) 9.33 (br s, 1H), 8.86 (d, J = 7.5 Hz, 1H), 8.28 (s, 1H), 7.99 (dd, J = 7.9, 1.76 Hz, 1H), 7.52 (d, J = 7.9 Hz, 1H), 7.26-7.33 (m, 2H), 7.16 -7.25 (m, 3H), 5.06 (s, 2H), 4.36-4.47 (m, 1H), 3.64 (s, 3H), 2.62-2.83 (m, 2H), 2.03-2.18 (m, 2H); ESI-MS m/z 354 [M+H]; HPLC purity: 99.62% (220nm), 100% (254nm).

Example 26. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-phenylalaninate (6-026)

This compound was prepared from (S)-phenylalanine methyl ester and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.31 (s, 1H), 8.87 ( d, J = 7.8 Hz, 1H), 8.18 (s, 1H), 7.84-7.92 (m, 1H), 7.48 (d, J = 8.0 Hz, 1H), 7.25-7.31 (m, 4H), 7.16-7.22 (m, 1H), 5.03 (s, 2H), 4.62-4.74 (m, 1H), 3.64 (s, 3H), 3.05-3.22 (m, 2H);

ESI-MS m/z 340 [M+H]+; HPLC purity: 99.08% (220nm), 99.48% (254nm).

Example 27. Methyl (S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-4-phenylbutanoate (6-027)

This compound was prepared from (S)-2-amino-4-phenylbutanoic acid and Acid-01 in a similar manner to Example 25.

1H NMR (400 MHz, DMSO-cfe) 9.33 (s, 1H), 8.86 (d, J = 7.3 Hz, 1H), 8.28 (s, 1H), 7.99 (d, J = 7.8 Hz, 1H), 7.52 ( d, J = 7.78 Hz, 1H), 7.26-7.32 (m, 2H), 7.17-7.25 (m, 3H), 5.06 (s, 2H), 4.35-4.47 (m, 1H), 3.64 (s, 3H) , 2.61-2.83 (m, 2H), 2.03-2.17 (m, 2H); ESI-MS m/z 354 [M+H]+; HPLC purity: 99.39% (220nm).

Example 28. Methyl (S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-5-phenylpentanoate (6-028)

This compound was prepared from (S)-2-amino-5-phenylpentanoic acid and Acid-01 in a similar manner to Example 25 followed by chiral separation by chiral HPLC. 1H NMR (400 MHz, DMSO-cfe) 9.32 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 8.25 (s, 1H), 7.96 (dd, J = 7.9, 1.13 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.24-7.31 (m, 2H), 7.13-7.22 (m, 3H), 5.05 (s, 2H), 4.48 (q, J = 7.3 Hz, 1H), 3.64 (s, 3H), 2.61 (t, J = 6.65 Hz, 2H), 1.83 (q, J = 7.53 Hz, 2H), 1.60-1.75 (m, 2H); ESI-MS m/z 389 [M+Na]+; HPLC purity: 98.89% (220nm), 98.87% (254nm).

Example 29. Methyl (R)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-5-phenylpentanoate (6-029)

This compound was prepared from (R)-2-amino-5-phenylpentanoic acid and Acid-01 in a similar manner to Example 25 followed by chiral separation by chiral HPLC. 1H NMR (400 MHz, DMSO-cfe) 9.31 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 8.24 (s, 1H), 7.96 (dd, J = 7.9, 1.38 Hz, 1H), 7.50 (d, J = 7.8 Hz, 1H), 7.24-7.30 (m, 2H), 7.14-7.21 (m, 3H), 5.05 (s, 2H), 4.48 (q, J = 7.2 Hz, 1H), 3.64 (s, 3H), 2.61 (t, J = 6.7 Hz, 2H), 1.82 (q, J = 7.7 Hz, 2H), 1.60-1.76 (m, 2H); ESI-MS m/z 368 [M+H]+; HPLC purity: 98.74% (220nm), 98.50% (254nm).

Example 30. 4-Fluorobenzyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-030)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine, and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.34 (s, 1H), 8.67 (d, J =7.6 Hz, 1H), 8.24 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.45 (dd, J =8.4, 5.6 Hz, 2H), 7.21 (t, J =9.6 Hz, 2H), 5.19 (d, J = 12.4 Hz, 1H), 5.13 (d, J = 12.4 Hz, 1H), 5.06 (s, 2H), 4.33 (t, J =7.7 Hz, 1H), 2.21 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H); ESI-MS m/z 386 [M+H]+; HPLC purity: 99.85% (220nm), 100% (254nm).

Example 31. 2,4-Difluorobenzyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-031)

This compound was prepared from 2,4-difluorobenzylalcohol, N-BOC-(S)-valine, and Acid-01 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.34 (s, 1H), 8.63 (d, J =7.6 Hz, 1H), 8.20 (s, 1H), 7.91 (d, J = 8.0 Hz, 1H), 7.55-7.46 (m, 4H), 5.18 (d, J = 12.4 Hz, 1H ), 5.11 (d, J = 12.4 Hz, 1H), 5.02 (s, 2H), 4.28 (t, J = 7.7 Hz, 1H), 2.15 (m, 1H), 0.93 (d, J = 6.8 Hz, 3H ), 0.88 (d, J = 6.8 Hz, 3H); ESI-MS m/z 404 [M+H]+; HPLC purity: 99.32% (220nm), 100% (254nm).

Example 32. Benzyl (1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-032)

This compound was prepared from Acid-02 (WO 2012109164 A1) and (S)-valine benzyl ester in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.62 (d, J = 7.6 Hz, 1H), 8.17 (s, 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.53-7.30 (m, 5H), 5.19 (d , J =12.4 Hz, 1H), 5.15 (d, J =12.4 Hz, 1H), 2.22 (m, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H ); ESI-MS m/z 396 [M+H]; HPLC purity: 98.56% (220nm), 100% (254nm).

Example 33. 4-Fluorobenzyl (1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-033)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine, and Acid-02 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.62 (d, J = 7.6 Hz, 1H), 8.16 (s, 1H), 7.93 (d, J = 8.0 Hz, 1H), 7.52 (d, J = 8.0 Hz, 1H), 7.45 (m, 2H), 7.20 (t, J = 8.8 Hz, 2H), 5.20 (d, J = 12.4 Hz, 1H), 5.10 (d, J = 12.4 Hz, 1H) 4.34 (t, J = 7.6 Hz, 1H), 2.20 (t, J = 5.6 Hz, 1H), 1.47 (s, 6H), 0.99 (d, J = 5.6 Hz, 3H), 0.90 (d, J = 5.6 Hz, 3H); ESI-MS m/z 414 [M+H]+; HPLC purity: 97.59% (220nm), 100% (254nm).

Example 342,4-Difluorobenzyl(1-hydroxy-3,3-dimethyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-034) This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine, and Acid-02 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-da) 8.61 (d, J = 8.0 Hz , 1H), 8.14 (s, 1H), 7.90 (d, J = 8.0 Hz, 1H), 7.56 (q, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.29 (t , J = 8.0 Hz, 1H), 7.29 (t, J = 8.0 Hz, 1H), 5.16 (q, J = 12.4, 26.8 Hz, 2H), 4.31 (t, J = 7.6 Hz, 1H), 2.17 (m , 1H), 1.46 (s, 6H 0.98 (d, J = 7.2 Hz, 3H), 0.88 (d, J = 7.2 Hz, 3H)-; ESI-MS m/z 432 [M+H]+; HPLC purity : 98.84% (220nm), 100% (254nm).

Example 35. Benzyl (7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-035)

This compound was prepared from benzyl alcohol, N-BOC-(S)-valine and Acid-03 in a similar manner to Example 1. ESI-MS m/z 386 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 36. 4-Fluorobenzyl (7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-036)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-03 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.38 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 7.65-7.47 (m, 1H), 7.45-7.43 (m, 2H), 7.30 (d, J = 7.6 Hz, 1H), 7.23-7.19 (m, 2H) , 5.20-5.11 (m, 2H), 5.04 (s, 2H), 4.38-4.35 (m, 1H), 2.19-2.12 (m, 1H), 0.94-.091 (m, 6H); ESI-MS m/z 404 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 37. 2,4-Difluorobenzyl(7-fluoro-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-037)

This compound was prepared from 2,4-difluorobenzylalcohol, N-BOC-(S)-valine, and Acid-03 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.57 (d, J = 7.6 Hz, 1H), 7.66-7.57 (m, 2H), 7.32-7.29 (m, 2H), 7.28-7.12 (m, 1H), 5.24-5.13 (m, 2H), 5.04 (s, 2H), 4.36- 4.32 (m, 1H), 2.18-2.09 (m, 1H), 0.93-0.90 (m, 6H); ESI-MS m/z 422 [M+H]+; HPLC purity: 95.88% (220nm), 97.81% (254nm).

Example 38. Benzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-038)

This compound was prepared from 04-acid benzyl ester and (S)-valine in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.03 (s, 1H), 8.57 ( d, J = 8.0 Hz, 1H), 7.41-7.23 (m, 7H), 5.16 (dd, J = 12.4 Hz, J = 20.0 Hz, 2H), 4.96 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 2.43 (s, 3H), 2.18-2.13 (m, 1H), 0.94 (d, J = 5.6 Hz, 6H); ESI-MS m/z 382 [M+H]; HPLC purity: 100% (220nm), 100% (254nm).

Example 39. 2,4-Difluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-039)

This compound was prepared from 2,4-difluorobenzylalcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.57 (d, J = 7.6 Hz, 1H), 7.66-7.57 (m, 2H), 7.32-7.29 (m, 2H), 7.28-7.12 (m, 1H), 5.24-5.13 (m, 2H), 5.04 (s, 2H), 4.36- 4.32 (m, 1H), 2.18-2.09 (m, 1H), 0.93-0.90 (m, 6H); ESI-MS m/z 418 [M+H]+; HPLC purity: 95.88% (220nm), 97.81% (254nm).

Example 40. 4-Chlorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-040)

This compound was prepared from 4-chlorobenzylalcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.01 (s, 1H), 8.56 (d, J =7.5 Hz, 1H), 7.43 (s, 4H), 7.32 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 5.15 (d, J = 4.0 Hz , 2H), 4.95 (s, 2H), 4.33 (t, J = 7.3 Hz, 1H), 2.42 (s, 3 H), 2.19 -1.99 (m, 1 H), 0.92 (d, J = 6.6 Hz, 6H) ESI-MS m/z 416 [M+H]+; HPLC purity: 97.85% (220nm), 98.66% (254nm).

Example 41. 4-Trifluoromethylbenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-041)

This compound was prepared from 4-trifluoromethylbenzylalcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.59 ( d, J = 7.5 Hz, 1H), 7.74 (d, J = 7.9 Hz, 2H), 7.62 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 7.5 Hz, 1H), 5.27 (s, 2H), 4.95 (s, 2H) 4.36 (t, J = 7.3 Hz, 1H), 2.41 (s, 3H), 2.16 (dq, J = 13.56, 6.65 Hz , 1H), 1.00-0.88 (m, 6H); ESI-MS m/z 450 [M+H]+; HPLC purity: 98.98% (220nm), 100% (254nm).

Example 42. 3-Fluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-042)

This compound was prepared from 3-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-da) 9.06 (s, 1H), 8.63 (d, J = 7.8 Hz, 1H), 7.44 (q, J = 7.36 Hz, 1H), 7.35 (d, J = 7.8 Hz, 1H), 7.26 (d, J = 6.8 Hz, 3H), 7.21 - 7.13 (m, 1H), 5.21 (s, 2H), 4.98 (s, 2H), 4.37 (t, J =7.2 Hz, 1H), 2.44 (s, 3H), 2.23-2.13 (m, 1H), 0.97 -0.94 (m, 6H); ESI-MS m/z 400 [M+H]+; HPLC purity: 96.98% (220nm), 100% (254nm).

Example 43. 3-Chlorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-043)

This compound was prepared from 3-chlorobenzyl alcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.59 (d, J = 7.50 Hz, 1H), 7.47 (s, 1H), 7.43 - 7.30 (m, 4H), 7.22 (d, J = 7.5 Hz, 1H), 5.17 (d, J =1.8 Hz, 2H ), 4.95 (s, 2H), 4.35 (t, J = 7.3 Hz, 1H), 2.42 (s, 3H), 2.21 - 2.09 (m, 1H), 0.93 (d, J = 6.62,); ESI-MS m/z 416 [M+H]+; HPLC purity: 99.67% (220nm), 100% (254nm).

Example 44. 4-Cyanobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-044)

This compound was prepared from 4-cyanobenzylalcohol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.06 (s, 1H), 8.65 (d, J = 7.5 Hz, 1H), 7.88 (d, J = 8.28 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 7.8 Hz, 1H), 7.25 (d , J = 7.8 Hz, 1H), 5.29 (s, 2H), 4.98 (s, 2H), 4.38 (t, J = 7.2 Hz, 1H), 2.44 (s, 3H), 2.24 - 2.12 (m, 1H), 0.96 (dd, J = 6.7, 1.63 Hz, 6H); ESI-MS m/z 407 [M+H]+; HPLC purity: 97.14% (220nm), 98.60% (254nm).

Example 45. 4-Fluorobenzyl (S)-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-2-phenylacetate (6-045)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-phenylglycine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6)9.13 (d, J =7.1 Hz, 1H), 9.01 (s, 1H), 7.45 (d, J = 6.2 Hz, 2H), 7.39 - 7.29 (m, 6H), 7.20 (d, J = 7.9 Hz, 1H), 7.14 (t, J = 8.8 Hz, 2H), 5.67 (d, J = 7.5 Hz, 1H), 5.15 (s, 2H), 4.95 (s, 2H), 2.43 (s, 3H); ESI-MS m/z 434 [M+H]+; HPLC purity: 99.70% (220nm), 100% (254nm).

Example 46. 3-Trifluoromethylbenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-046)

This compound was prepared from 3-trifluoromethylbenzyl alcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-da) 9.01 (s, 1H), 8.59 (d, J = 7.5 Hz, 1H), 7.56 - 7.83 (m, 4H), 7.15 -7.39 (m, 2H), 5.27 (d, J = 1.8 Hz, 2H), 4.95 (s, 2H), 4.35 (t, J = 7.1 Hz, 1H), 2.41 (s, 3H), 2.15 (dd, J = 13.5, 6.8 Hz, 1H), 0.93 (d, J = 6.17 Hz, 6H); ESI-MS m/z 450 [M+H]+; HPLC purity: 99.75% (220nm), 100% (254nm).

Example 47. 3-Cyanobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-047)

This compound was prepared from 3-cyanobenzyl alcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.60 (d, J = 7.9 Hz, 1H), 7.87 (s, 1H), 7.82 - 7.70 (m, 2H), 7.63 - 7.56 (m, 1H), 7.33 (d, J = 7.9 Hz, 1H), 7.22 (d, J = 7.9 Hz, 1H), 5.22 (s, 2H), 4.95 (s, 2H), 4.35 (t, J = 7.3 Hz, 1H), 2.41 (s, 3H), 2.16 (dq, J = 13.45, 6.69 Hz, 1H), 0.94 (d, J = 6.6 Hz, 6H); ESI-MS m/z 407 [M+H]+; HPLC purity: 96.71% (220nm), 94.02% (254nm).

Example 48. 3,5-Difluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-048)

This compound was prepared from 3,5-difluorobenzylalcohol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.02 (s, 1H) , 8.62 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 7.9 Hz, 1H), 7.27-7.03 (m, 4H), 5.19 (s, 2H), 4.95 (s, 2H), 4.36 ( t, J = 7.3 Hz, 1H), 2.42 (s, 3H), 2.16 (d, J = 6.6 Hz, 1H), 0.95 (dd, J = 6.84, 2.4 Hz, 6H); ESI-MS m/z 418 [M+H]+; HPLC purity: 99.91% (220nm), 100% (254nm).

Example 49. 4-Fluoro-3-(trifluoromethyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-049)

This compound was prepared from 4-fluoro-3-trifluoromethylbenzylalcohol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 7.93- 7.76 (m, 2H), 7.68 - 7.49 (m, 1H), 7.38 - 7.16 (m, 2H), 5.24 (s, 2H), 4.95 (s, 2H), 4.33 (t, J = 7.3 Hz, 1H), 2.40 (s, 3H), 2.14 (d, J = 6.6 Hz, 1H), 0.93 (d, J = 7.1 Hz, 6H); ESI-MS m/z 468 [M+H]+; HPLC purity: 96.57% (220nm), 97.23% (254nm).

Example 50. 4-Fluorobenzyl (S)-2-cyclopropyl-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)acetate (6-050 )

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-cidopropylglycine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.03 (d, J =5.3 Hz, 1H), 8.83 (s., 1H), 7.45 (s., 2H), 7.36 (d, J = 7.1 Hz, 1H), 7.28-7.14 (m, 3H), 5.24- 5.09 (m, 2H ), 4.97 (d, J = 4.4 Hz, 2H), 3.79 (s, 1H), 2.44 (d, J = 4.9 Hz, 3H), 1.19 (s, 1H), 0.60-0.35 (m, 4H); ESI-MS m/z 398 [M+H]+; HPLC purity: 99.52% (220nm), 100% (254nm).

Example 51. 3-Chloro-4-fluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-051)

This compound was prepared from 3-chloro-4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) 9.02 (s , 1H), 8.58 (d, J = 7.5 Hz, 1H), 7.64 (d, J =7.5 Hz, 1H), 7.43 (d, J = 7.5 Hz, 2H), 7.33 (d, J =7.9 Hz, 1H ), 7.22 (d, J = 7.9 Hz, 1H), 5.16 (s, 2H), 4.96 (s, 2H), 4.33 (t, J = 7.3 Hz, 1H), 2.42 (s, 3H), 2.23 - 2.07 (m, 1H), 0.97 - 0.86 (m, 6H); ESI-MS m/z 434 [M+H]+; HPLC purity: 95.56% (220nm), 98.25% (254nm).

Example 52. 4-Fluorobenzyl(7-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-052)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine, and Acid-05 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.98 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 7.47-7.43 (m, 2H), 7.29 (d, J = 8.0 Hz, 1H), 7.23-7.18 (m, 3H), 5.14 (s, 2H), 4.96 ( s, 2H), 4.34 (t, J = 7.6 Hz, 1H), 2.86-2.80 (m, 2H), 2.13 (t, J = 6.8 Hz, 1H), 1.06 (t, J = 6.8 Hz, 3H), 0.92 (d, J = 4.4 Hz, 6H); ESI-MS m/z 414 [M+H]+; HPLC purity: 96.93% (220nm), 95.38% (254nm).

Example 53. Benzyl (7-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-053)

This compound was prepared from (S)-valine benzyl ester and Acid-05 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 8.98 (s, 1H), 8.58 (d , J = 8.0 Hz, 1H), 7.40-7.30 (m, 5H), 7.21 (d, J = 7.6 Hz, 1H), 5.16 (s, 2H), 4.96 (s, 2H), 4.36 (t, J = 7.6 Hz, 1H), 2.84 (q, J = 7.2 Hz, J = 7.6 Hz, 2H), 2.16 (t, J = 6.8 Hz, 1H), 1.07 (t, J = 7.2 Hz, 3H), 0.92 (d , J = 6.8Hz, 6H); ESI-MS m/z 396 [M+H]+; HPLC purity: 97.21% (220nm), 95.72% (254nm).

Example 54. 4-Trifluoromethoxybenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-054)

This compound was prepared from 4-trifluoromethoxybenzylalcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-da) 9.01 (s, 1H), 8.57 (d, J = 7.9 Hz, 1H), 7.53 (d, J =8.4 Hz, 2H), 7.44 - 7.30 (m, 3H) 7.21 (d, J = 7.5 Hz, 1H), 5.36 - 5.08 (m, 2H ), 4.96 (s, 2H), 4.34 (t, J = 7.3 Hz, 1H), 2.41 (s, 3H), 2.22 -2.07 (m, 1H), 0.93 (d, J = 6.17 Hz, 6H); ESI-MS m/z 466 [M+H]+; HPLC purity: 99.63% (220nm), 95.53% (254nm).

Example 55. 3-Trifluoromethoxybenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-055)

This compound was prepared from 3-trifluoromethoxybenzyl alcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.59 (d, J = 7.50 Hz, 1H), 7.54 - 7.49 (m, 1H), 7.46 -7.38 (m, 2H) 7.36 - 7.31 (m, 2H) 7.33 (d, J = 7.50Hz, 2H) 7.21 ( d, J = 7.9 Hz, 1H) 5.29 - 5.17 (m, 2H) 4.96 (s, 2H) 4.35 (t, J = 7.3 Hz, 1H) 2.42 (s, 3H)2.15 (dq, J =13.51, 6.82 Hz , 1H) 0.94 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H); ESI-MS m/z 466 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 56. 4-(Methylsulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-056)

This compound was prepared from 4-(methylsulfonyl)benzylalcohol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) 9.03 (s, 1H ), 8.61 (d, J = 7.5 Hz, 1H), 7.93 (d, J =7.9 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.43 - 7.19 (m, 2H), 5.29 (s , 2H), 4.96 (s, 2H), 4.38 (t, J = 7.1 Hz, 1H), 3.21 (s, 3H), 2.43 (s, 3H), 2.25-2.09 (m, 1H), 0.96 (d, J = 6.2Hz, 6H); ESI-MS m/z 460 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 57. 4-Fluorobenzyl(7-cyclopropyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-057)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine, and acid-06 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) 8.90 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 7.47 (t, J = 6.0 Hz, 2H), 7.23 (d, J = 8.0 Hz, 4H), 5.19 (s, 2H), 4.96 (s, 2H), 4.34 (t, J = 7.2 Hz, 1H), 2.15-2.13 (m, 2H), 0.94 (d, J = 4.4 Hz, 6H), 0.77 (d, J = 5.2 Hz, 4H); ESI-MS m/z 426 [M+H]+; HPLC purity: 98.89% (220nm), 99.55% (254nm).

Example 58. Benzyl (7-cidopropiM-hydroxM,3-dihydrobenzo[c][1,2]oxaborol-6-carbonN)-L-vaNnate (6-058)

This compound was prepared from (S)-valine benzyl ester and Acid-06 in a similar manner to the last step of Example 1.1H NMR (400 MHz, DMSO-da) 8.90 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.41-7.35 (m, 5H), 7.22 (t, J = 5.2 Hz, 2H), 5.21 5.14 (m, 2H), 4.96 (s, 2H), 4.35 (t, J = 7.2 Hz , 1H), 2.16-2.14 (m, 2H), 0.96-0.94 (m, 6H), 0.79-0.76 (m, 4H); ESI-MS m/z 408 [M+H]+; HPLC purity: 99.97% (220nm), 100% (254nm).

Example 59. 4-Fluorobenzyl (S)-2-cyclobutyl-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)acetate (6-059 )

This compound was prepared from 4-fluorobenzyl alcohol, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclobutylacetic acid, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO -cfe) 9.02 (s, 1H), 8.55 (d, J = 7.5 Hz, 1H), 7.42 (dd, J = 8.38, 5.7 Hz, 2H), 7.32 (d, J = 7.9 Hz, 1H), 7.26 - 7.14 (m, 3H), 5.23 - 5.02 (m, 2H), 4.95 (s, 2H), 4.39 (dd, J = 9.3, 7.5 Hz, 1H), 2.73 - 2.61 (m, 1H), 2.42 (s, 3H), 2.04-1.71 (m, 6H); ESI-MS m/z 412 [M+H]+; HPLC purity: 98.85% (220nm), 94.70% (254nm).

Example 60. 4-Fluorobenzyl (S)-2-cyclopentyl-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)acetate (6-060 )

This compound was prepared from 4-fluorobenzyl alcohol, (S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid, and Acid-04 in a similar manner to Example 1. 1H NMR (400 m Hz, d Ms Oc^ ) 9.01 (s, 1H), 8.64 (d, J = 7.5 Hz, 1H), 7.44 (dd, J = 8.6, 5.51 Hz, 2H), 7.31 (d, J = 7.9 Hz, 1H), 7.24-7.15 (m, 3H), 5.19-5.07 (m, 2H), 4.95 (s, 2H), 4.29 (t, J = 8.2 Hz, 1H), 2.41 (s, 3H), 2.29-2.19 (m, 1H), 1.80-1.38 (m, 8H); ESI-MS m/z 426 [M+H]+; HPLC purity: 98.85% (220nm), 94.70% (254nm).

Example 61. 4-Fluorobenzyl(3,7-dimethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-061)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine and Acid-07 in a similar manner to Example 1.1H NMR (400 MHz, DMSO-cfe) 8.98 (s, 1H), 8.60 (d , J = 8.0 Hz, 1H), 7.48-7.44 (m, 2H), 7.33 (d, J = 6.0 Hz, 1H), 7.23-7.20 (m, 3H), 5.20-5.11 (m, 3H), 4.32 ( s, 1H), 2.50 (s, 3H), 2.16-2.11 (m, 1H), 1.39 (d, J = 6.0 Hz, 3H ), 0.93 (d, J = 6.4 Hz, 6H); ESI-MS m/z 414 [M+H]+; HPLC purity: 99.31% (220nm), 99.01% (254nm).

Example 62. 4-Fluorobenzyl(1-hydroxy-7-isopropyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-062)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-08 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.15 (s, 1H), 8.58 (d, J= 8.0 Hz, 1H), 7.46-7.43 (m, 2H), 7.22-7.16 (m, 4H), 5.17-5.10 (m, 2H), 4.96 (s, 2H), 4.34 (t, J = 7.2 Hz, 1H), 3.19 (t, J = 6.4 Hz, 1H), 2.15-2.10 (m, 1H), 1.29-1.24 (m, 6H), 0.87 (t, J = 3.2 Hz, 6H); ESI-MS m/z 428 [M+H]+; HPLC purity: 99.85% (220nm), 100% (254nm).

Example 63. Benzyl (1-hydroxy-7-isopropyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-063)

This compound was prepared from (S)-valine benzyl ester and Acid-08 in a similar manner to the last step of Example 1.1H NMR (400 MHz, DMSO-cf) 9.15 (s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 7.40-7.34 (m, 5H), 7.19 (t, J = 1.6 Hz, 2H), 5.12 (d, J = 2.4 Hz, 1H); 4.96 (s, 2H), 4.35 (t, J = 6.8 Hz, 1H), 3.24-3.17 (m, 1H), 2.17-2.12 (m, 1H), 1.29-1.23 (m, 6H), 0.91 (d, J = 6.8Hz, 6H); ESI-MS m/z 410 [M+H]+; HPLC purity: 99.91% (220nm), 100% (254nm).

Example 64. 4-Fluorobenzyl(1-hydroxy-7-propyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-064)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-09 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.97 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 7.48-7.45 (m, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.24-7.21 (m, 3H), 5.12 (s, 2H), 4.97 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 2.86-2.80 (m, 2H), 2.18-2.12 (m, 1H), 1.50 (s, 2H), 0.93 (d, J = 3.2 Hz, 6H), 0.81 (t, J = 7.2 Hz, 3H); ESI-MS m/z 428 [M+H]+; HPLC purity: 96.59% (220nm), 93.52% (254nm).

Example 65. Benzyl(1-hydroxy-7-propyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-065)

This compound was prepared from (S)-valine benzyl ester and acid-09 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 8.97 (s, 1H), 8.59 (d , J = 7.6 Hz, 1H), 7.41-7.24 (m, 7H), 5.17 (s, 2H), 4.97 (s, 2H), 4.36 (t, J = 6.8 Hz, 1H), 2.85 (t, J = 8.0 Hz, 2H), 2.18-2.13 (m, 1H), 1.50 (s, 2H), 0.93 (d, J = 3.2 Hz, 6H), 0.81 (t, J = 7.6 Hz, 3H); ESI-MS m/z 410 [M+H]+; HPLC purity: 96.53% (220nm), 94.89% (254nm).

Example 66

This compound was prepared from 4-fluorobenzyl alcohol, 1-((tert-butoxycarbonyl)amino)cyclobutane-1-carboxylic Acid, and 04-Acid in a similar manner to Example 1. 1H NMR (400 Mh z , DMSO-cfe ) 9.02 (d, J = 5.7 Hz, 2H), 7.43 (dd, J = 8.4, 5.7 Hz, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.26 - 7.14 (m, 3H), 5.14 ( s, 2H), 4.96 (s, 2H), 2.60 - 2.54 (m, 2H), 2.40 (s, 3H), 2.35 - 2.22 (m, 2H), 2.04 - 1.78 (m, 2H); ESI-MS m/z 398 [M+H]+; HPLC purity: 98.46% (220nm), 97.78% (254nm).

Example 67. (5-Fluoropyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-067)

A mixture of 14 (500 mg, 4 mmol) and LiAlH ⁴ (202 mg, 5 mmol) in THF (10 mL) was degassed and purged with N ² 3 times, then the mixture was stirred at 0°C for 12 h under N ² atmosphere. The reaction mixture was quenched with saturated potassium sodium tartrate (0.8 mL) at 15°C and then filtered. The mixture was diluted with H ² O (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 15 (236 mg, 52%) as a yellow solid. 1H NMR (400 MHz, DMSO-cfe) 8.43 (d, J = 2.8 Hz, 1H), 7.45-7.41 (m, 1H), 7.31-7.27 (m, 1H), 4.76 (s, 2H). A mixture of 15 (1 g, 8 mmol), DCC (3 g, 16 mmol), DMAP (96 mg, 786 umol), and N-BOC-(S)-valine (2 g, 9 mmol) in DCM (5 ml) was degassed and purged with N ² 3 times, and then the mixture was stirred at 25°C for 12 h under N ² atmosphere. The reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by column chromatography (SO ² , PE/EtOAc = 5:1) to give 16 (1.3 g, 51%) as a yellow liquid. 1H NMR (400 MHz, DMSO-cfe) 8.55 (s, 1H), 7.71-7.83 (m, 1H), 7.54-7.51 (m, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.22-5.13 (m, 2H), 3.91 (t, J =7.2 Hz, 1H), 2.06-2.02 (m, 1H), 1.38 (s, 9H), 0.87 (d, J = 6.4 Hz, 6H).

To a mixture of 16 (1.3 g, 4 mmol) in EtOAc (20 mL) was added HCl/EtOAc (6 M, 10 mL). The mixture was stirred at 15°C for 2 h under N ² atmosphere. The reaction mixture was concentrated under reduced pressure to give 17 (800 mg, 77%) as a yellow solid.

1H NMR (400 MHz, DMSO-cfe) 8.58 (d, J = 2.4 Hz, 1H), 8.51 (s, 2H), 7.84-7.80 (m, 1H), 7.65-7.61 (m, 1H), 5.36-5.27 (m, 2H), 4.04-4.00 (m, 1H), 2.23-2.19 (m, 1H), 0.99-0.94 (m, 6H).

Compound 6-067 was prepared from 17 and Acid-04 in a similar manner to the last step of Example 1.1 H NMR (400 MHz, DMSO-cfe) 8.96 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 8.55 (d, J = 2.4 Hz, 1H) 7.78 (td, J = 8.8, 3.6 Hz, 1H) 7.56 (dd, J = 8.4, 4.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 4.95 (s, 2H), 4.37 (t, J = 7.2 Hz, 1H), 2.42 (s, 3H), 2.21-2.12 (m, 1H), 0.96 (dd, J = 6.8, 2.4 Hz, 6H); ESI-MS m/z 401 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 68 4-Fluorobenzyl 1-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)cyclopropane-1-carboxylate (6-068)

This compound was prepared from 4-fluorobenzyl alcohol, 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carboxylic acid, and Acid-04 in a similar manner to Example 1. 1H NMR (400 Mh z , DMSO-cfe ) 9.02 (s, 1H), 8.83 (s, 1H), 7.47 - 7.38 (m, 2H), 7.31 (d, J = 7.5 Hz, 1H), 7.20 (t, J = 7.7 Hz, 3H), 5.12 ( s, 2H), 4.95 (s, 2H), 2.39 (s, 3H), 1.45 (s, 2H), 1.17 (s, 2H); ESI-MS m/z 384 [M+H]+; HPLC purity: 97.30% (220nm), 98.64% (254nm).

Example 69. Methyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-069)

This compound was prepared from (S)-valine methyl ester and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.01 (s, 1H), 8.52 ( d, J = 7.5 Hz, 1H), 7.35 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 4.96 (s, 2H), 4.29 (t, J = 7.3 Hz, 1H), 3.66 (s, 3H), 2.45 (s, 3H), 2.11 (d, J = 7.1 Hz, 1H), 0.94 (d, J = 4.2 Hz, 3H), 0.92 (d, J = 4.2 Hz, 3H); ESI-MS m/z 306 [M+H]+; HPLC purity: 99.96% (220nm), 100% (254nm).

Example 70. 4-Fluorobenzyl (1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6070)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-10 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.23 (s, 1H), 8.88 (d, J =8.0 Hz, 1H), 7.70 (d, J =8.0 Hz, 1H), 7.47 (dd, J = 8.4, 6.4 Hz, 2H), 7.41 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 8.8 Hz, 2H), 5.23-5.21 (m, 2H), 5.08 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 2.18-2.09 (m, 1H), 0.98 -0.81 (m, 6H); ESI-MS m/z 454 [M+H]+; HPLC purity: 98.51% (220nm), 98.43% (254nm).

Example 71. Benzyl (1-hydroxy-7-(trifluoromethyl)-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-071)

This compound was prepared from (S)-valine benzyl ester and Acid-10 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.21 (br s, 1H), 8.87 ( d, J = 7.6 Hz, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.40 (s, 6H), 525-5.13 (m, 2H), 5.08 (s, 2H), 4.37 (t, J = 6.8 Hz, 1H), 2.16-2.14 (m, 1H), 0.92 (d, J = 3.6 Hz, 6H); ESI-MS m/z 436 [M+H]+; HPLC purity: 98.07% (220nm), 93.03% (254nm).

Example 72 )

A mixture of 18 (5.00 g, 19.1 mmol), N-methylpiperazine (5.73 g, 57.2 mmol), Pd ² (dba ⁾³ (3.49 g, 3.82 mmol), Cs ² CO ³ (12.4 g, 38.2 mmol), and 2 ,2'-bis(diphenylphosphino)-1,1'-binaphthalene (3.56 g, 5.72 mmol) in 1,4-dioxane (5 mL) was degassed and purged with N ² 3 times, then the mixture was stirred at 80°C for 18 h under N ² atmosphere. The mixture was then cooled to 15°C, filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20:1) to give 19(1.40 g, 31%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) 7.60 (s, 1H), 7.52 (d, J = 7.5 Hz, 1H), 7.34-7.30 (m, 1H), 7.12 (dd, J = 7.7, 2.4 Hz, 1H ), 3.91 (s, 3H), 3.29-3.25 (m, 4H), 2.62-2.65 (m, 4H), 2.37 (s, 3H). To a solution of 19 (1.40 g, 5.98 mmol) in THF (10 mL) was added LiAlH ⁴ (454 mg, 12.0 mmol) at 0°C. The mixture was stirred at 70°C for 2h. The mixture was cooled to 0°C and quenched with saturated sodium potassium tartrate solution (3 mL), the precipitate formed was collected and filtered to remove the precipitate. The organic phase was concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH=20:1) to give 20 (530 mg, 43%) as a brown solid. 1H NMR (400 MHz, DMSO-cfe) 7.26 (s, 1H), 6.96 (s, 1H), 6.91 -6.80 (m, 2H), 4.66 (s, 2H), 3.32 - 3.05 (m, 4H), 2.66 - 2.48 (m, 4H), 2.36 (s, 3H). To a solution of 20 (530 mg, 2.57 mmol) in DCM (10 mL) was added N-Boc-(S)-valine (670 mg, 3.08 mmol), DCC (795 mg, 3.86 mmol), and DMAP (62.8 mg , 0.514mmol). The mixture was stirred at 15°C for 24h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (DCM/MeOH = 20:1) to give 21 (600mg, 58%) as a brown solid. To a solution of 21 (200 mg, 0.493 mmol) in EtOAc (5 mL) was added HCl/EtOAc (4 M, 2 mL). The mixture was stirred at 15°C for 15h. The mixture was then concentrated in vacuo, the formed precipitate collected by filtration to give 22 (120 mg, 71%) as a yellow solid.

Compound 6-072 was prepared from 22 and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.05 (s, 1H), 8.59 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.27-7.15 (m, 2H), 6.94 (s, 1H), 6.90 (d, J =8.3 Hz, 1H), 6.79 (d, J =7.3 Hz, 1H), 5.11 (d, J = 7.3 Hz, 2H), 4.98 (s, 2H), 4.35 (t, J =7.3 Hz, 1H), 3.16-3.07 (m, 4H), 2.45 ( s, 3H), 2.43-2.38 (m, 4H), 2.21 (s, 3H) 2.17(brs, 1H), 1.00-0.92 (m, 6H); ESI-MS m/z 480 [M+H]; HPLC purity: 98.26% (220nm), 99.95% (254nm).

Example 73. 4-Fluorobenzyl (7-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6073)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-11 in a similar manner to Example 1.1H NMR (400 MHz, DMSO-da) 9.18 (s, 1H), 8.83 (d, J = 7.6 Hz, 1H), 7.62 (d, J = 7.6 Hz, 1H), 7.54-7.39 (m, 3H), 7.22 (t, J = 8.8 Hz, 2H), 7.04 (t, J = 54.8 Hz, 1H), 5.22-5.12 (m, 2H), 5.07 (s, 2H), 4.39-4.31 (m, 1H), 2.15 (td, J = 13.6, 6.4 Hz, 1H), 0.97-0.83 (m , 6H); ESI-MS m/z 436 [M+H]+; HPLC purity: 98.74% (220nm), 100% (254nm).

Example 74. 4-Fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-threoninate (6-074)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(L)-threonine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cf) 9.06 (s, 1H), 8.16 (d, J = 8.3 Hz, 1H), 7.52 - 7.38 (m, 3H), 7.30 - 7.15 (m, 3H), 5.25-5.10 (m, 2H), 4.98 (s, 2H), 4.84 (d, J = 6.5 Hz, 1H), 4.52 (dd, J = 3.6, 8.2 Hz, 1H), 4.20 (brs, 1H), 2.46 (s, 3H), 1.16 (d, J = 6.3 Hz, 3H); ESI-MS m/z 402 [M+H]+; HPLC purity: 98.36% (220nm), 97.90% (254nm).

Example 75. 4-(Methylsulfonamido)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6075)

To a solution of 23 (5.0 g, 30 mmol) and pyridine (7.0 g, 91 mmol) in DCM (20 mL) was added MsCl (4.0 g, 36 mmol) dropwise at 0°C under N ² atmosphere. The reaction mixture was stirred at 0°C for 0.4h. The reaction mixture was quenched with H ² O (50 mL) at 0°C and then extracted with DCM (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 24 (7.0 g, 95%) as a red solid. 1H NMR (400 MHz, DMSO-d6) 8.03 (d, J = 8.4 Hz, 2H), 7.28 (d, J = 6.0 Hz, 2H), 4.37 (m, 2H), 3.08 (s, 3H), 1.39 ( t, J = 6.4 Hz, 3H). To a mixture of 24 (2.0 g, 8.0 mmol) in THF (30 mL) was added LiAlH ⁴ (468 mg, 12.0 mmol) slowly at 0°C, and then the reaction mixture was stirred at 15°C for 12 h in N ² atmosphere. The reaction mixture was quenched with 0.5 mL of saturated potassium sodium. After filtering, the filtrate was concentrated under reduced pressure to give 25 (300mg, 18%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 9.62 (s, 1H), 7.27 (d, J = 8.0 Hz, 2H), 7.16 (d, J= 8.0 Hz, 2H), 5.12 (s, 1H), 4.44 ( d, J = 4.4 Hz, 2H), 2.94 (s, 3H). A mixture of 25 (500 mg, 2.50 mmol), N-Boc-(S)-valine (1.2 g, 5.5 mmol), dCc (1 g, 5 mmol), and DMAP (30 mg, 0.25 mmol) in DCM ( 10 mL) was stirred at 15°C for 12 h under N ² atmosphere. After filtering, the filtrate was concentrated under reduced pressure. The crude was purified by column chromatography (petroleum ether/EtOAC = 2:1) to give 26 (600 mg, crude) as a white solid. To a solution of 26 (600 mg) in EtOAc (100 mL) was added HCl/EtOAc (6 M, 2 mL) and then the mixture was stirred at 15°C for 2 h under N ² atmosphere. The reaction mixture was concentrated under reduced pressure to give 27 (400 mg, crude) as a white solid.

Compound 6-075 was prepared from 27 and Acid-04 in a similar manner to the last step of Example 1.1 H NMR (400 MHz, DMSO-cfe) 9.80 (s, 1H), 9.03 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.41-7.30 (m, 3H), 7.26-7.14 (m, 3H), 5.19-5.05 (m, 2H), 4.97 (s, 2H), 4.33 (t, J = 7.2 Hz, 1H), 3.01-2.94 (m, 3H), 2.43 (s, 3H)2.14 (q, J =13.6, 6.8 Hz, 1H), 1.00-0.89 (m, 6H); ESI-MS m/z 475 [M+H]; HPLC purity: 97.85% (220nm), 92.14% (254nm).

Example 76. 4-(Methylsulfonyl)benzyl(7-ethyl-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-076)

This compound was prepared from 4-fluorobenzylalcohol, N-BOC-(S)-valine, and Acid-05 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 8.99 (s, 1H), 8.64 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 8.0 Hz, 1H), 7.22 (d , J = 8.0 Hz, 1H), 5.32-5.25 (m, 2H), 4.96 (s, 2H), 4.38 (t, J = 7.2 Hz, 1H), 3.20 (s, 3H), 2.86-2.81 (m, 2H), 2.20-2.15 (s, 1H), 1.06 (t, J = 7.2 Hz, 3H), 1.00 (d, J = 7.2 Hz, 3H), 0.95 (d, J = 7.0 Hz, 3H); ESI-MS m/z 474 [M+H]+; HPLC purity: 98.27% (220nm), 98.06% (254nm).

Example 77. 4-Fluorobenzyl O-benzyl-N-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-threoninate (6-077)

To a solution of (tert-butoxycarbonyl)-L-threonine (1.00 g, 4.56 mmol) in DMF (15 mL) was added NaH (401 mg, 10.0 mmol) at -15°C. Bromomethylbenzene (858 mg, 5.02 mmol) was then added. The mixture was stirred at 15°C for 10h. LCMS showed that the desired mass was detected. The reaction mixture was quenched by addition of 1M HCl aqueous solution to pH=4 and extracted with 15 mL EtOAc (5 mL x 3). The combined organic layers were washed with 5 mL of brine, dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Luna C8 100 x 305u; liquid phase: [A-TFA/H ² O = 0.075% v/v; B-ACN] B%: 35%-55%, 12 min] ). After purification by preparative HPLC, the eluant was concentrated to remove organic solvent. The residual aqueous solution was lyophilized to give 29 (1.00 g, 71%) as a white solid. To a solution of 29 (1.00 g, 3.23 mmol) in DMF (15 mL) was added Cs ² CO ³ (1.16 g, 3.55 mmol) at 0°C. 1-(Bromomethyl)-4-fluoro-benzene (672 mg, 3.55 mmol) was then added. The mixture was stirred at 15°C for 8h. HPLC indicated that the reaction was complete and the desired mass was detected according to LCMS. Mix The reaction mixture was quenched by the addition of 15 mL of water and extracted with 45 mL of EtOAc (15 mL x 3). The combined organic layers were washed with 20 mL of brine, dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 x 25 5u; liquid phase: [A-NH ⁴ HCO ³ 10 mM in H ² O; B-ACN]B%:45%-75%, 20 min] ). After purification by preparative HPLC, the eluant was concentrated to remove organic solvent. The residual aqueous solution was lyophilized to give 30 (610 mg, 45%) as a yellow oil. 1H NMR (400 MHz, DMSO-cfe) 7.32 - 7.25 (m, 5H), 7.18 (d, J = 7.5 Hz, 2H), 6.97 (t, J = 8.6 Hz, 2H), 5.30 (d, J = 9.7 Hz, 1H), 5.08 (s, 2H), 4.50 (d, J =11.9 Hz, 1H), 4.34 (dd, J =1.8, 9.7 Hz, 1H), 4.26 (d, J =11.9 Hz, 1H), 4.18-4.10 (m, 1H), 1.45 (s, 9H), 1.26 (d, J = 6.2 Hz, 3H). A mixture of 30 (501mg, 1.20mmol) and HCl/EtOAc (4M, 3.00mL) was stirred at 15°C for 5h. TLC showed the reaction to be complete. The reaction mixture was concentrated under reduced pressure to give 31 (410 mg, 97% yield) as a yellow solid.

Compound 6-077 was prepared from 31 and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6) 9.02 (s, 1H), 8.52 (d, J = 8.4 Hz, 1H), 7.45-7.35 (m, 3H), 7.32 -7.20 (m, 6H), 7.13 (t, J = 8.8 Hz, 2H), 5.16 (s, 2H), 4.97 (s, 2H), 4.75 (dd, J = 7.09, 4.0 Hz, 1H), 4.53 (d, J =11.9 Hz, 1H), 4.37 (d, J =11.9 Hz, 1H), 4.17-4.09 (m, 1H), 2.45 (s , 3H), 1.23 (d, J = 6.2 Hz, 3H); ESI-MS m/z 492 [M+H]; HPLC purity: 100% (220nm), 100% (254nm).

Example 78. Methyl O-benzyl-N-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-threoninate (6-078)

To a solution of 29 (600 mg, 1.94 mmol) in DMF (3 mL) was added Cs ² CO ³ (695 mg, 2.13 mmol) at 0°C. Iodomethane (303 mg, 2.13 mmol) was then added. The mixture was stirred at 15°C for 10h. HPLC indicated that the reaction was complete and the desired mass was detected according to LCMS. The reaction mixture was quenched by the addition of 15 mL of water and extracted with EtOAc (15 mL x 3). The combined organic layers were washed with 15 mL of brine, dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Waters Xbridge 150 x 255u; liquid phase: [A-NH ⁴ HCO ³ 10 mM in H ² O; B-ACN] B%: 30%-60%, 20 min]) . After purification by preparative HPLC, the eluant was concentrated to remove organic solvent. The residual aqueous solution was lyophilized to give 32 (520 mg, 83%) as a yellow oil. 1H NMR (400 MHz, DMSO-cfe) 7.36 - 7.24 (m, 5H), 5.31 (d, J = 9.3 Hz, 1H), 4.57 (d, J =11.9 Hz, 1H), 4.41 - 4.28 (m, 2H ), 4.16-4.09 (m, 1H), 3.68 (s, 3H), 1.46 (s, 9H), 1.27 (d, J = 6.2 Hz, 3H).

Compound 6-078 was prepared from 32 and Acid-04 in a similar manner to the last two steps of Example 77. 1H NMR (400 MHz, DMSO-cf) 9.03 (br s, 1H), 8.47 (d, J = 8.4 Hz, 1H), 7.39 (d, J = 7.9 Hz, 1H), 7.36 - 7.18 (m, 6H), 4.97 (s, 2H), 4.69 (dd, J = 4.2, 8.2 Hz, 1H), 4.59 - 4.53 (m, 1H), 4.43 (d, J = 11.9 Hz, 1H), 4.09 (dd, J = 4.4, 6.2 Hz, 1H), 3.66 (s, 3H), 2.48 (br s, 3H), 1.23 (d, J = 6.2 Hz, 3H); ESI-MS m/z 398 [M+H]; HPLC purity: 99.60% (220nm), 97.96% (254nm).

Example 79. Benzyl (7-(difluoromethyl)-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-079)

This compound was prepared from (S)-valine benzyl ester and Acid-11 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.18 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.44-7.31 (m, 5H), 7.05 (t, J = 54.8 Hz, 1H ), 5.23-5.14 (m, 2H), 5.07 (s, 2H), 4.37 (t, J = 7.2 Hz, 1H), 2.17 (dq, J = 13.6, 6.6 Hz, 1H), 0.94 (d, J = 6.4Hz, 6H); ESI-MS m/z 418 [M+H]+; HPLC urity: 99.93% (220nm), 100% (254nm).

Example 80. 3-(Methylsulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-080)

To a solution of 34 (2.00 g, 9.99 mmol) in THF (10 mL) was added LIAIH ⁴ (758 mg, 20.0 mmol) at 0°C. The mixture was stirred at 15°C for 14h. The mixture was cooled to 0°C and quenched with saturated sodium potassium tartrate solution (2 mL), the precipitate formed was collected and filtered to remove the precipitate. The organic phase was concentrated in vacuo to give 35 (1.40 g, 63%). 1H NMR (400 MHz, CDCh) 7.97 (s, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.63-7.53 (m, 1H), 4.82 ( d, J = 5.7 Hz, 2H), 3.07 (s, 3H).

To a solution of 35 (1.03 g, 5.52 mmol) in DCM (10 mL) was added N-Boc-(S)-valine (1.00 g, 4.60 mmol), DCC (1.42 g, 6.90 mmol), and DMAP (56.2 mg , 0.460mmol). The mixture was stirred at 15°C for 14h. The reaction mixture was filtered and concentrated under reduced pressure (40°C) to give a residue. The residue was purified by column chromatography (SO ² , petroleum ether/ethyl acetate = 2:1) to give 36 (1.20 g, 68%) and was obtained as a yellow oil.

To a solution of 36 (400 mg, 1.04 mmol) in EtOAc(10 mL) was added HCl/EtOAc(4 M, 5.2 mL). The mixture was stirred at 15°C for 1.5h. Then, the reaction mixture was concentrated under reduced pressure (40°C) to remove the solvent. The formed precipitate was then collected, filtered to give 37 (280 mg, 84%) and obtained as a white solid. 1H NMR (400 MHz, DMSO-d6) 8.64 (s, 3H), 8.00 (s, 1H), 7.91 (d, J = 7.9 Hz, 1H), 7.80 (d, J = 7.9 Hz, 1H), 7.72 - 7.65 (m, 1H), 5.35 (s, 2H), 3.94 (d, J = 4.4 Hz, 1H), 3.22 (s, 3H), 2.20 (m, 1H), 0.97 (d, J = 7.2 Hz, 3H ), 0.93 (d, J = 7.2 Hz, 3H).

Compound 6-080 was prepared from 37 and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6) 9.04 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 7.98 (s, 1H), 7.90 (d, J = 7.9 Hz, 1H), 7.77 (d, J = 7.9 Hz, 1H), 7.71 - 7.65 (m, 1H), 7.34 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.9 Hz, 1H), 5.30 (s, 2H), 4.97 (s, 2H), 4.37 (t, J = 7.1 Hz, 1H), 3.21 (s , 3H), 2.43 (s, 3H), 2.17 (dd, J = 13.5, 6.84 Hz, 1H), 0.95 (d, J = 6.6 Hz, 6H); ESI-MS m/z 460 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 81 3-((dimethylamino)methyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6081)

To a solution of 38 (4.58 g, 20.0 mmol) and Me ² NH HCl (2.45 g, 30.0 mmol) in CH ³ CN (50 mL) was added K ² CO ³ (11.1 g, 80.0 mmol). The mixture was stirred at 60°C for 12h. The reaction mixture was filtered, the residue was washed with EtOAc (20 mL), and then the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (DCM:MeOH = 10:1) to give 39 (1.6 g, 41%) as a yellow oil. 1H NMR (400 MHz, CDCla) 7.96 (s, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H) , 3.90 (s, 3H), 3.45 (s, 2H), 2.23 (s, 6H). To a solution of 39 (1.60 g, 8.28 mmol) in THF (30 mL) was added LiAlH ⁴ (471 mg, 12.0 mmol) in portions at 0°C. The mixture was stirred at 15°C for 12h. The reaction mixture was quenched with saturated potassium sodium tartrate (1.8 mL) at 0°C and then filtered. The filtrate was concentrated under reduced pressure to give 40 (1.32 g, 96%) as a yellow oil.

Compound 6-081 was prepared from 40 and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.81 (s, 1H), 9.02 (s, 1H), 8.56 (d , J =7.6 Hz, 1H), 7.52 (s, 1H), 7.48 (s, 2H), 7.32 (d, J = 7.2 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.20 (s , 2H), 4.95 (s, 2H), 4.33 (t, J = 7.6 Hz, 1H), 4.25 (d, J = 4.0 Hz, 3H), 2.69 (s, 6H), 2.41 (s, 3H), 2.18 -2.12 (m, 1H), 0.94-0.92 (m, 6H); ESI-MS m/z 439 [M+H]+; HPLC purity: 97.97% (220nm), 98.89% (254nm).

Example 82. 3-((4-Methylpiperazin-1-yl)methyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-082)

This compound was prepared from 38,1-methylpiperazine and Acid-04 in a similar manner to Example 81 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.57 (d, J = 8.0 Hz, 1H ), 7.44 (s, 2H), 7.49 (s, 2H), 7.32 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.18 (s, 2H), 4.95 (s , 2H), 4.33 (t, J = 7.2 Hz, 1H), 3.16 (d, J =8.8 Hz, 2H), 2.78 (s, 3H), 2.31 (s, 3H), 2.18-2.12 (m, 1H) , 0.95-0.92 (m, 6H); ESI-MS m/z 494 [M+H]+; HPLC purity: 98.25% (220nm), 100% (254nm).

Example 83. 3-(Morpholinomethyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-083)

This compound was prepared from 38,1-methylpiperazine and Acid-04 in a similar manner to Example 81.1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H ), 7.56 (s, 2H), 7.49 (s, 2H), 7.31 (d, J = 7.2 Hz, 1H) 7.21 (d, J = 7.6 Hz, 1H), 5.19 (s, 2H), 4.95 (s, 2H), 4.35-4.31 (m, 3H), 3.88 (d, J =12.8 Hz, 2H), 3.66 (s, 2H), 3.18 (s, 2H), 3.04 (s, 2H), 2.31 (s, 3H ), 2.18-2.13 (m, 1H), 0.93-0.92 (m, 6H); ESI-MS m/z 481 [M+H]+; HPLC purity: 96.43% (220nm), 94.91% (254nm).

Example 84. 4-(Methylsulfonyl)benzyl(1-hydroxy-7-isopropyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-084)

This compound was prepared from 4-(methylsulfonyl)benzylalcohol, N-BOC-(S)-valine, and Acid-08 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6)9.15 (s, 1H ), 8.64 (d, J = 8.0 Hz, 1H), 7.92 (d, J =8.4 Hz, 2H), 7.66 (d, J =8.0 Hz, 2H), 7.21-7.18 (m, 2H), 5.28 (s , 2H), 4.96 (s, 2H), 4.38 (t, J = 7.6 Hz, 1H), 3.20-3.18 (m, 4H), 2.19-2.14 (m, 1H), 1.27 (t, J = 6.4 Hz, 6H), 0.94 (d, J = 6.8 Hz, 6H); ESI-MS m/z 488 [M+H]+; HPLC purity: 98.60% (220nm), 97.23% (254nm).

Example 85. 4-((4-Methylpiperazin-1-yl)sulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-085)

To a solution of 41 (1.0 g, 4.0 mmol) and Et3N (1.3 g, 13 mmol) in DCM (10 mL) was added 1-methylpiperazine (1.1 g, 11 mmol) at 0°C. The reaction mixture was stirred for one hour and then washed with H ² O (10 mL x 4), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 42 (700 mg, 55%) as a white solid. 1H NMR (400 MHz, CDCh) 8.19 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H), 3.97 (s, 3H), 3.07 (br s, 4H), 2.48 (t , J = 4.8 Hz, 4H), 2.27 (s, 3h). To a solution of 42 (700 mg, 2.40 mmol) in THF (20 mL) was added LiAlH ⁴ (134 mg, 3.60 mmol). The mixture was stirred at 0°C for 12h. 0.5 mL of saturated potassium sodium tartrate was added to the reaction mixture and stirred for 10 min. The mixture was then filtered and concentrated under reduced pressure to give 43 (300 mg, 48%) as a white solid. 1H NMR (400 MHz, CDCl3) 7.74 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 4.78 (s, 2H), 3.04 (br s, 4H), 2.48 (t , J = 4.4 Hz, 4H), 2.27 (s, 3H).

Compound 6-085 was prepared from 43 and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.05 (s, 1H), 8.65 (d, J = 7.6 Hz, 1H ), 7.81 (d, J = 8.4 Hz, 2H), 7.72 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1 H) , 5.39-5.27 (m, 2H), 4.98 (s, 2H), 4.38 (t, J = 7.2 Hz, 1H), 3.79 (d, J =12.4 Hz, 4H), 3.15 (d, J = 9.2 Hz, 4H), 2.76 (s, 3H), 2.45 (s, 1H), 2.22-2.15 (m, 1H), 0.98 (d, J =6.4, 3.6 Hz, 6H); ESI-MS m/z 544 [M+H]+; HPLC purity: 92.93% (220nm), 88.77% (254nm).

Example 86. 4-(Morpholinosulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6086)

Compound 6-086 was prepared in a similar manner to Example 85 using morpholine in place of 1-methylpiperazine.

1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.60 (d, J =7.6 Hz, 1H), 7.73 (d, J =7.6 Hz, 2H), 7.67 (d, J =8.0 Hz, 2H), 7.32 (d, J =7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.29 (s, 2H), 4.95 (s, 2H), 4.36 (t, J =7.2 Hz, 1H), 3.60 (s, 4H), 2.83 (s, 4H), 2.42 (s, 3H), 2.19-2.14 (m, 1H), 0.93 (d, J =6.4 Hz, 6H); ESI-MS m/z 531 [M+H]+; HPLC purity: 99.94% (220nm), 100% (254nm).

Example 87. 4-Fluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-D-valinate (6-087)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(R)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cC6) 9.03 (s, 1H), 8.56 (d, J = 7.5 Hz, 1H), 7.46 (dd, J = 8.4, 5.73 Hz, 2H), 7.33 (d, J = 7.5 Hz, 1H), 7.27-7.15 (m, 3H), 5.16 (d, J =7.5 Hz, 2H), 4.97 (s, 2H), 4.34 (t, J = 7.1 Hz, 1H) , 2.45- 2.41(m, 3H), 2.14 (dd, J = 13.5, 6.8 Hz, 1H), 1.02 - 0.82 (m, 6H); ESI-MS m/z400 [M+H]+; HPLC purity: 98.94% (220nm), 99.52% (254nm).

Example 88. 4-Fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-allothreoninate (6-088)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(L)-allothreonine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-da) 9.02 (s, 1H), 8.46 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 6.0 Hz, 2H), 7.33 (d, J =8.0 Hz, 1H), 7.23-7.16 (m, 3H), 5.13 (d, J = 3.2 Hz, 2H), 5.04 (d, J =5.6 Hz, 1H), 4.95 (s, 2H), 4.38 (t, J = 6.8 Hz, 1H), 4.00 (t, J = 6.0 Hz, 1H), 2.41 (s, 3H), 1.16 (d, J = 6.0 Hz, 3H); ESI-MS m/z 402 [M+H]+; HPLC purity: 96.86% (220nm), 95.47% (254nm).

Example 89. 4-(Isopropylsulfinyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-089)

To a solution of 43 (5.00 g, 40.3 mmol) in DMSO (25 mL) was added propane-2-thiol (3.38 g, 44.3 mmol) and K2CO3 (11.1 g, 80.6 mmol). The mixture was stirred at 100°C for 16h. The mixture was cooled to 15°C and poured into ice water (30 mL) and stirred for 20 minutes. The aqueous phase was extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (15 ml x 2), dried over Na 2 SO ^4, filtered and concentrated under vacuum to give 44 (6.3 g, 87%) as a colorless oil. 1H NMR (400 MHz, DMSO d) 9.93 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 3.79-3.72 (s, 1H), 1.31 (d, J =7.6Hz, 6H). To a solution of 44 (3.00 g, 16.6 mmol) in THF (20 mL) and MeOH (4 mL) was added NaBH4 (755 mg, 20.0 mmol) in portions at 0°C, then the mixture was stirred at 15°C. for 2 hours. The reaction mixture was quenched with water (20 mL) at 0°C and then extracted with DCM (20 mL x 3). The combined organic layers over Na 2 SO ⁴ dried, filtered and concentrated under reduced pressure to give 45 (2.99 g, 99%) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.38 (d, J = 8.0 Hz, 2H), 7.295 (d, J = 8.0 Hz, 2H), 4.66 (s, 2H), 3.39-3.32 (m, 1H), 1.28 ( d, J = 6.4 Hz, 6H).

A mixture of 45 (2.9 g, 15.9 mmol), DCC (5.91 g, 28.6 mmol), DMAP (194 mg, 1.6 umol), and N-Boc-(S)-valine (3.46 g, 15.9 mmol) in DCM (20 ml) was stirred at 15°C for 10 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether:EtOAc = 5:1) to give 46 (4.73 g, 78%) as a white solid. 1H NMR (400 MHz, CDCh ) 7.36 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 5.13 (q, J = 17.2, 12.0, Hz, 2H), 4.25 (dd , J = 4.0 Hz, 1H), 3.43-3.35 (m, 1H), 2.16-2.11 (m, 1H), 1.43 (s, 9H), 1.29 (d, J = 6.8 Hz, 6H), 0.93 (d, J = 7.2 Hz, 3H), 0.84 (d, J = 6.4 Hz, 3H). To a solution of 46 (1.00 g, 2.62 mmol) in DCM (20 mL) was added mCPBA (1.13 g, 6.55 mmol) in portions, then the mixture was stirred at 15°C for 10 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc = 2:1) to give 47 (0.82 g, 78.73% yield) as a colorless oil.

Compound 6-089 was prepared from 47 and Acid-04 in a similar manner to the last two steps of Example 1. 1H NMR (400 MHz, DMSO-d6) 9.06 (s, 1H), 8.62 (d, J =7.2 Hz, 1H), 7.62 (s, 4H), 7.34 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 5.26 (d, J = 7.2 Hz, 2H), 4.98 (s, 2H), 4.36 (t, J = 6.8 Hz, 1H), 2.98-2.92 (m, 1H), 2.42 (s, 3H), 2.20 2.15 (m, 1H), 1.17 (d, J = 6.8 Hz, 3H), 0.95-0.91 (m, 9H); ESI-MS m/z 472 [M+H]+; HPLC purity: 99.29% (220nm), 99.18% (254nm).

Example 90. 4-(Methylsulfinyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-090)

Compound 6-090 was prepared from 4-(methylthio)benzylalcohol and Acid-04 in a manner similar to the last two steps of Example 89. 1H NMR (400 MHz, DMSO-cf) 9.01 (s, 1H), 8.58 (d, J = 7.5 Hz, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.62 - 7.55 (m, 2H), 7.32 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 7.9- Hz, 1H), 5.23 (s, 2H), 4.95 (s, 2H), 4.35 (s, 1H), 2.72 (s, 3H), 2.41 (s, 3H), 2.19 - 2.12 (m, 1H ), 0.94 (d, J = 6.6- Hz, 6H); ESI-MS m/z 444 [M+H]+; HPLC purity: 99.44% (220nm), 100% (254nm).

Example 91 4-fluorobenzyl 3-fluoro-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate 4-fluorobenzyl (6-091)

This compound was prepared from 2-((tert-butoxycarbonyl)amino)-3-fluoro-3-methylbutanoic acid, 4-fluorobenzyl alcohol, and Acid-04 in a similar manner to Example 1. 1H NMR (400 Mh z , DMSO-cfe) 9.03 (s, 1H), 8.82 (d, J = 7.9 Hz, 1H), 7.46 (dd, J = 8.2, 6.0 Hz, 2H), 7.33 (d, J = 7.9 Hz, 1H), 7.26 -7.16 (m, 3H), 5.20 (d, J = 6.2 Hz, 2H), 4.97 (s, 2H), 4.76 (dd, J = 16.1, 8.2 Hz, 1H), 2.42 (s, 3H), 1.54 - 1.38 (m, 6H); ESI-MS m/z 418[M+H]+; HPLC purity: 98.90% (220nm), 95.67% (254nm).

Example 92. 4-(isopropylsulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-092)

To a solution of 46 (1.00 g, 2.62 mmol) in DCM (20 mL) was added mCPBA (2.13 g, 10.5 mmol) in portions, then the mixture was stirred at 15°C for 10 h. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative TLC (petroleum ether:EtOAc = 5:1) to give 48 (0.95 g, 88%) as a colorless oil. 1H NMR (400 MHz, CDCfe) 7.87 (d, J =8.4 Hz, 2H), 7.54 (d, J = 8.0 Hz, 2H), 5.29 (s, 2H), 4.14-4.09 (m, 1H), 3.22- 3.13 (m, 1H), 2.20-2.13 (m, 1H), 1.43 (s, 9H), 1.28 (d, J = 6.4 Hz, 6H), 0.96 (d, J = 6.8 Hz, 3H), 0.87 (d , J0 =6.4Hz, 3H).

Compound 6-092 was prepared from 48 and Acid-04 in a similar manner to the last two steps of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.01 (s, 1H), 8.60 (d, J = 6.8 Hz, 1H), 7.84 (d, J = 6.4 Hz, 2H), 7.67 (d, J = 6.4 Hz, 2H), 7.32 (d, J = 6.4 Hz, 1H), 7.21 (d, J = 7.2 Hz, 1H), 5.29 (s, 2H), 4.95 (s, 2H), 4.38-4.35 (m, 1H), 3.43-3.37 (m, 1H), 2.40 (s, 3H), 2.19-2.14 (m, 1H), 1.12 (d, J = 5.6 Hz, 6H), 0.93 (d, J = 6.4 Hz, 6H); ESI-MS m/z 488 [M+H]+; HPLC purity: 99.98% (220nm), 100% (254nm).

Example 93. 4-(Ethylsulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-093)

Compound 6-093 was prepared in a similar manner to Examples 89 and 92 using ethanethiol in place of 2-propanethiol. 1H NMR (400 MHz, DMSO-cfe) 9.03 (s, 1H), 8.62 (d, J = 7.2 Hz, 1H), 7.89 (d, J =7.2 Hz, 2H), 7.68 (d, J = 7.6 Hz, 2H), 7.35 (d, J = 7.6 Hz, 1H), 7.23 (d, J = 7.2 Hz, 1H), 5.30 (s, 2H), 4.97 (s, 2H), 4.38 (m, 1H), 3.30 ( t, J = 6.8 Hz, 2H), 2.42 (s, 3H), 2.19-2.07 (m, 1H), 1.08 (t, J = 6.4 Hz, 3H), 0.96 (d, J = 6.0 Hz, 6H); ESI-MS m/z 474 [M+H]+; HPLC purity: 99.86% (220nm), 100% (254nm).

Example 94. 4-(Ethylsulfinyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-094)

Compound 6-093 was prepared in a similar manner to Example 89 using ethanethiol in place of 2-propanethiol. 1H NMR (400 MHz, DMSO-cfe) 9.04 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 7.68-7.59 (m, 4H), 7.33 (d, J = 7.2 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.28-5.21 (m, 2H), 4.97 (s, 2H), 4.38-4.34 (m, 1H), 3.04-2.99 (m, 1H), 2.78-2.74 ( m, 1H), 2.42 (s, 3H), 2.18-2.16 (m, 1H), 1.05 (t, J = 7.6 Hz, 3H), 0.95-0.93 (m, 6H); ESI-MS m/z 458 [M+H]+; HPLC purity: 99.56% (220nm), 100% (254nm).

Example 95 2-(pyrrolidin-1-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-095)

This compound was prepared from 2-pyrrolidinoethanol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.07 (s, 1H), 8.67 (br s, 1,H), 7.40 (br s, 1H), 7.26 (br s, 1H), 4.97 (s, 2H), 4.48 (m, 1H), 4.40 (m, 2H), 3.65-3.52 ( m, 4H), 3.07 (m, 2H), 2.47 (s, 3H), 2.21 (m, 1H), 2.02-1.81 (m, 4H), 0.97 (s, 6H); ESI-MS m/z 389 [M+H]+; HPLC purity: 94.65% (220nm), 94.92% (254nm).

Example 96 2-(4-methylpiperazin-1-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6096 )

This compound was prepared from 2-(4-methylpiperazin-1-yl)ethan-1-ol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) 9.09 (s, 1H), 8.64 (d, J = 7.2 Hz, 1H), 7.40 (d, J =7.2 Hz, 1H), 7.26 (d, J = 7.2 Hz, 1H), 4.97 (s, 2H), 4.48 (s, 1H), 4.41 (d, J = 7.2 Hz, 2H), 3.37 (s, 8H), 2.80 (s, 3H) , 2.47 (s, 3H), 2.22 2.18 (m, 1H), 0.97 (d, J = 6.0 Hz, 6H); ESI-MS m/z 418 [M+H]+; HPLC purity: 99.13% (220nm), 99.60% (254nm).

Example 97 )

To a solution of N-BOC-(L)-allothreonine (300 mg, 1.37 mmol) in DMF (5 mL) was added NaHCO ³ (345 mg, 4.10 mmol) at 0°C. 4-Fluorobenzyl bromide (310 mg, 1.64 mmo) was then added dropwise and the reaction mixture stirred at 15°C for 12 h. The reaction mixture was diluted with water (20 ml) and then extracted with MTBE (15 ml x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 49 (400 mg, 89%) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.34 (t, J = 4.8 Hz, 2H), 7.04 (t, J =8.8 Hz, 2H), 5.45 (s, 1H), 5.20-5.12 (m, 2H), 4.39 ( s, 1H), 4.13 (s, 1H), 1.43 (s, 9H), 1.14 (s, 3H). To a solution of 49 (600 mg, 1.83 mmol) in toluene (15 mL) was added Ag ² O (1.27 g, 5.50 mmol) and 4-fluorobenzyl bromide (415 mg, 2.20 mmol). The mixture was stirred at 120°C for 12h. After filtering, the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (TFA condition) to give 50 (50mg, 5.2%) as a yellow oil.

Compound 6-097 was prepared from 50 and Acid-04 in a similar manner to the last two steps of Example 1. 1H NMR (400 MHz, DMSO-d6) 9.02 (s, 1H), 8.66 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.6 Hz, 2H), 7.32-7.29 (m, 3H), 7.22 (d, J = 7.6 Hz, 1H), 7.17-7.12 (m, 4H), 5.14 (d, J = 2.8 Hz, 2H), 4.95 (s, 2H), 4.74 (t, J = 7.6 Hz, 1H), 4.53-4.43 (m, 2H), 3.95 (t, J = 6.0 Hz, 1H) , 2.40 (s, 3H), 1.19 (d, J = 6.4 Hz, 3H); ESI-MS m/z 510 [M+H]+; HPLC purity: 99.37% (220nm), 100% (254nm).

Example 98. 3,4-(S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate difluorobenzyl (6-098)

This compound was prepared from 3,4-difluorobenzylalcohol, (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid, and Acid-04 in a similar manner to Example 1. 1H NMR ( 400 m Hz, DMSO-cfe) 9.07 (s, 1h), 8.29 (d, J = 8.0 Hz, 1H), 7.56-7.41 (m, 2H), 7.37 (d, J = 7.2 Hz, 1H), 7.29 ( s, 1H), 7.25 (d, J = 7.2 Hz, 1H), 5.17 (s, 2H), 4.97 (s, 2H), 4.87 (s, 1H), 4.47 (d, J = 8.0 Hz, 1H), 2.43 (s, 3H), 1.25 (s, 3H), 1.24 (s, 3H); ESI-MS m/z 434 [M+H]+; HPLC purity: 96.90% (220nm), 95.33% (254nm).

Example 99. 3,5-Difluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate (6-099)

This compound was prepared from 3,5-difluorobenzylalcohol, (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid, and Acid-04 in a similar manner to Example 1. 1H NMR ( 400 MHz, DMSO-cfe) 9.07 (s, 1H), 8.34 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 7.2 Hz, 1H), 7.26 (d, J =8.0 Hz, 1H), 7.18 (d, J = 8.0 Hz, 3H), 5.23 (s, 2H), 5.00 (s, 2H), 4.92 (s, 1H), 4.51 (d, J = 8.0 Hz, 1H), 2.45 (s, 3H ), 1.27 (d, J = 5.6 Hz, 6H); ESI-MS m/z 434 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 100. 3,4,5-trifluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-100)

To a mixture of N-Boc-(S)-valine (300 mg, 1.38 mmol) and NaHCO3 (347 mg, 4.14 mmol) in DMF (3 mL) was added 51 (341 mg, 1.52 mmol) at 0°C. The mixture was stirred at 15°C for 14h. Then water (5 ml) was added, the mixture was extracted with MTBE (5 ml x 3). The combined organic layer was washed with brine (2 mL x 3), dried over Na ² SO ⁴ , filtered and concentrated in vacuo to give crude 52 (1.4 g) as a brown oil.

Compound 6-100 was prepared from 52 and Acid-04 in a similar manner to the last two steps of Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.04 (s, 1H), 8.64-8.63 (m , 1H), 7.42-7.36 (m, 3H), 7.34-7.23 (m, 1H), 5.21-5.14 (m, 2H), 4.97 (s, 2H), 4.38-4.36 (m, 1H), 2.20-2.15 (m, 1H), 2.43 (s, 3H), 0.97 (s, 3H), 0.95 (s, 3H); ESI-MS m/z 436 [M+H]+; HPLC purity: 99.52% (220nm), 100% (254nm).

Example 101. 3,4,5-Trifluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3 -methylbutanoate (6-101)

This compound was prepared from 3,4,5-trifluorobenzyl alcohol, (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid, and Acid-04 in a similar manner to Example 100.1 H NMR (400 MHz, DMSO-cfe) 9.05 (s, 1H), 8.32-8.30 (m, 1H), 7.43-7.37 (m, 3H), 7.26-7.24 (m, 1H), 5.19 (s, 2H) , 4.98 (s, 2H), 4.90 (s, 1H), 4.50-4.48 (m, 1H), 2.33 (s, 3H), 1.26 (s, 3H), 1.21 (s, 3H); ESI-MS m/z 434 [M+H]+; HPLC purity: 96.90% (220nm), 95.33% (254nm).

Example 102. 4-(Piperazine-1-carbonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-102)

To a solution of N-Boc-(S)-valine (5.0 g, 23 mmol) in DMF (100 mL) was added NaHCO ³ (5.8 g, 69 mmol) at 0°C. 53 (5.27 g, 23 mmol) was then added dropwise at 0°C and then the reaction mixture was stirred at 15°C for 12 h. The reaction mixture was diluted with water (200 ml) and then extracted with MTBE (100 ml x 3). The combined organic layers were washed with water ⁽¹⁰⁰ mL x ² ), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 54 (7.5 g, 88.7% yield) as a colorless oil. 1H NMR (400 MHz, CDCh) 8.02 (d, J = 7.6 Hz, 2H), 7.41 (d, J =8.0 Hz, 2H), 5.26-5.16 (m, 2H), 5.01-4.99 (m, 1H), 4.28-4.26 (m, 1H), 3.92 (s, 3H), 2.16-2.14 (m, 1H), 1.43 (s, 9H), 0.94 (d, J = 6.4 Hz, 3H), 0.85 (d, J = ^{6 8} Hz, 3H). To a solution of 54 (1.83 g, 5.00 mmol) in EtOAc (25 mL) was added HCl/EtOAc (4 M, 12.5 mL). The reaction solution was stirred at 15°C for 12h. The solvent was removed under reduced pressure to give 55 (1.4 g, 93%) as a white solid which was used in the next step without further purification. 1H NMR (400 MHz, CDCla) 8.97 (s, 2H), 8.00 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 5.31 5.21 (m, 2H), 3.95 (s , 1H), 3.90 (s, 3H), 2.45-2.44 (m, 1H), 1.11 (s, J = 7.2 Hz, 3H), 1.07 (d, J = ^6.8 Hz, 3H). To a solution of 55 (0.50 g, 2.6 mmol) in DMF (1 mL) was added HAt U (1.49 g, 3.9 mmol), TEA (1 g, 10.4 mmol), and Acid-04 (0.78 g, 2.6 mmol). The reaction mixture was stirred at 15°C for 2h. The mixture was poured into water (30 mL) and extracted with EtOAc (30 mL x 3). The combined organic layer was washed with brine (30 mL x 2), dried over Na ² SO ⁴ and concentrated under reduced pressure to give 56 (1.14 g, 79%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 9.02 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 7.94 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 7.6 Hz, 1H), 7.21 (d, J = 8.0 Hz, 1H), 5.25-5.22 (m, 2H), 4.95 (s, 2H), 3.84 (s, 4H), 2.42 (s, 3H), 2.16-2.15 (m, 1H), 0.94 (d, J = 6.4 Hz, ⁶ H).

To a solution of 56 (440 mg, 1.00 mmol) in DMF (10 mL) was added LiCl (424 mg, 10.0 mmol). The mixture was stirred at 140°C for 12h. The solvent was removed under reduced pressure and the residue was dissolved in water (20 mL), made pH = 5 with 3M HCl. The aqueous layer was extracted with EtOAc (20 mL x 3). The combined organic layer was dried and concentrated under reduced pressure. The residue was purified by preparative HPLC under acidic conditions to give 57 (30 mg, 7.1%) as a white solid. To a solution of 57 (30 mg, 0.07 mmol) in DMF (1 mL) was added HATU (40 mg, 0.10 mmol), TEA (21 mg, 0.21 mmol), and N-Boc-piperazine (14 mg, 0.077 mmol). and the reaction mixture was stirred at 15°C for two hours. The mixture was poured into water (5 mL) and extracted with EtOAc (5 mL x 3). The combined organic layer was dried over Na ² SO ⁴ and concentrated under reduced pressure to give ⁸⁸ (40 mg, 96%) as a white solid. MS (ESI): mass calculated for C ³¹ H ⁴⁰ BN ³ O ⁸ 593.29, m/z found 594.4 [M+H]+. A solution of 58 (40 mg, 0.067 mmol) and HCl/EtoAc (4 M, 0.84 mL) in EtOAc (1 mL) was stirred at 15 °C for 30 min. After filtration, the residue was purified by acidic preparative HPLC to give 6-102 (11 mg, 29%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 9.02 (s, 1H), 8.95 (s, 2H), 8.58 (d, J = 7.6 Hz, 1H), 7.47 (s, 4H), 7.33 (d, J = 7.6 Hz, 1H), 7.22 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.96 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 3.62 (s, 4H), 3.14 (s, 4H), 2.43 (s, 3H), 2.17-2.13 (m, 1H), 0.95 (d, J = 6.4 Hz, 3H), 0.94 (d, J = ^6.8 Hz, 3H); ESI-MS m/z 494 [M+H]+; HPLC purity: 95.40% (220nm), 96.27% (254nm).

Example 103. 4-((2-(Dimethylamino)ethyl)carbamoyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate ( 6-103)

Compound 6-103 was prepared in a similar manner to the 5th step of Example 102 using N1,N1-dimethylethane-1,2-diamine instead of N-Boc-piperazine. 1H NMR (400 MHz, DIVIDER) 9.02 (s, 1H), 8.56 (d, J = 7.6 Hz, 1H), 8.37 (t, J = 5.6 Hz, 1H), 7.80 (d, J = 8.0 Hz, 2H) , 7.44 (d, J = 8.4 Hz, 2H), 7.31 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 5.23 5.16 (m, 2H), 4.94 (s, 2H ), 4.34 (t, J = 7.2 Hz, 1H), 3.35-3.30 (m, 2H), 2.46-2.38 (m, 5H), 2.19 (s, 6H), 2.17-2.13 (m, 1H), 0.94- 0.88 (m, 6H); ESI-MS m/z 496 [M+H]+; HPLC purity: 96.95% (220nm), 98.33% (254nm).

Example 104. (1,1-Dioxido-3-oxo-2,3-dihydrobenzo[b]thiophen-5-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2 ]oxaborol-6-carbonyl)-L-valinate (6-104)

To a solution of 59 (5.0 g, 28 mmol) in DMF (20 mL) was added MeSNa (13 g, 36 mmol). The mixture was stirred at 80°C for 14h. The mixture was cooled to 15°C, poured into ice water (50 mL) and stirred for 30 min. A precipitate formed which was collected after filtration to give 60 (3.6 g, 62%) as an off-white solid. 1H NMR (400 MHz, CDCla) 8.24 (s, 1H), 8.17-8.14 (m, 1H), 7.33-7.30 (m, 1H), 3.94 (s, 3H) 2.61 (s, 3H). To a solution of 60 (3.00 g, 14.5 mmol) in DCM (20 mL) was added mCPBA (7.4 g, 36 mmol). The mixture was stirred at 15°C for 24h. Water (40 mL) was added to the mixture and it was stirred for 20 min. The organic phase was separated and washed with 5% NaOH (20 mL). The combined organic layer was washed with saturated Na ² SO ³ solution (20 mL x 3), brine (20 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated in vacuo to give 61 (2.9 g, 84%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 8.58 (s, 1H), 8.46 (d, J = 8.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 3.94 (s, 3H), 3.46 ( yes, 3H). To a solution of 61 (2.00 g, 8.36 mmol) in THF (20 mL) was added LiAlH ⁴ (634 mg, 16.7 mmol) at 0°C. The mixture was stirred at 15°C for 14h. The mixture was quenched with saturated sodium potassium tartrate solution (2 mL) and filtered. The filtrate was concentrated in vacuo to give crude 62 (1.2 g) as a yellow oil. 1H NMR (400 MHz, DMSO-cfe) 8.10 (d, J = 8.0 Hz, 1H), 7.98 (d, J =8.0 Hz, 1H), 7.3 (s, 1H), 5.64 (s, 1H), 4.65 ( s, 2H), 4.58 (s, 2H).

Compound 6-104 was prepared from 62, N-Boc-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.03 (s, 1H), 8.64 (d, J = 7.6 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.04 (s, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.39 (s, 2H), 4.97 (s, 2H), 4.63 (s, 2H), 4.44-4.38 (m, 1H), 2.44 (s , 3H), 2.21-2.16 (m, 1H), 0.96 (d, J = 6.8 Hz, 6H); ESI-MS m/z 484 [M+H]+; HPLC purity: 98.53% (220nm), 99.73% (254nm).

Example 105. 4-(4-Methylpiperazine-1-carbonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6- 105)

Compound 6-105 was prepared in a similar manner to Example 103 using N-methylpiperazine instead of N-Bocpiperazine. 1H NMR (400 MHz, DMSO-cfe) 9.03 (s, 1H), 8.57 (d, J =7.2 Hz, 1H), 7.48-7.43 (m, 4H), 7.31 (d, J =7.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 4.94 (s, 2H), 4.33 (t, J = 6.8 Hz, 1H), 3.52 (s, 4H), 3.05 (m, 4H ), 2.74 (d, J = 4.0 Hz, 3H), 2.29 (s, 3H), 2.13 (m, 1H), 0.94-0.92 (m, 6H); ESI-MS m/z 508[M+H]+; HPLC purity: 95.08% (220nm), 95.49% (254nm).

Example 106. 4-((2-(Dimethylamino)ethyl)(methyl)carbamoyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L -valinate (6-106)

Compound 6-106 was prepared in a similar manner to Example 103 using N1,N1,N2-trimethylethane-1,2-diamine instead of N-Boc-piperazine. 1H NMR (400 MHz, DMSO-cfe) 9.00 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.42 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.30 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 5.22-5.13 (m, 2H), 4.93 (s, 2H), 4.33 (t, J = 7.2 Hz, 1H), 3.49 (s, 1H), 3.22 (s, 1H), 2.92-2.86 (m, 3H), 2.62 (s, 1H), 2.42 (s, 3H), 2.29 (s, 1H), 2.17 -2.14 (m, 4H), 1.92 (s, 3H), 0.90 (d, J = 6.0 Hz, 6H); ESI-MS m/z 510[M+H]+; HPLC purity: 97.33% (220nm), 97.78% (254nm).

Example 107. 2-Methoxyethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-107)

To a solution of 6-003 (300 mg, 1.03 mmol) in DMF (4 mL) was added 2-chloroethyl methyl ether (116 mg, 1.24 mmol) and Cs ² COa (671 mg, 2.06 mmol). The mixture was stirred at 15°C for 6h. The mixture was purified by preparative HPLC (TFA condition) to give 6-107 (32 mg, 8.8%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 9.04 (s, 1H), 8.53-8.51 (m, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.33-4.26 (m, 1H), 4.25-4.14 (m, 2H) 3.54 (s, 2H), 3.28 (s, 3H), 2.47 (s, 3H), 2.16-2.11 (m , 1H), 0.96 (d, J = 8.0 Hz, 6H); ESI-MS m/z 350[M+H]+; HPLC purity: 98.34% (220nm), 96.76% (254nm).

Example 108. 4-Sulfamoylbenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-108)

To a solution of 63 (5.0 g, 25 mmol) in THF (100 mL) was added BH ³ -Me ² S (7.55 g, 100 mmol) dropwise at 0°C over 10 min. After the addition, the mixture was stirred at 10°C for 12h. The mixture was quenched by MeOH (100 mL) dropwise at 0°C and then concentrated under reduced pressure to give 64 (3 g, 64.47% yield) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 7.78 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.29 (s, 2H), 5.37 (s, 1H), 4.57 ( yes, 2H). A mixture of 64 (1.5 g, 8.0 mmol) and NaH (705 mg, 32 mmol) in DMF (7 mL) was degassed and purged with N ² 3 times and stirred for 12 min, then SEM-Cl ( 2.54 g, 15 mmol) to the mixture and stirred at 20°C for 1 h under N ² atmosphere. After quenching by addition of 50 mL NH ⁴ Cl at 10°C, the mixture was extracted with MTBE (50 mL x 2), the combined organic layers were washed with brine (50 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 2:1) to give 65 (2.2 g, 61%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 7.80 (d, J = 8.0 Hz, 2H), 7.49 (d, J = 8.0 Hz, 2H), 5.43 (t, J = 5.2 Hz, 1H), 4.71 (s, 4H), 4.57 (d, J = 4.8 Hz, 2H), 3.34 (t, J = 8.4 Hz, 4H), 0.74 (t, J = 8.0 Hz, 4H), -0.07 (s, 18 H).

A mixture of 65 (1 g, 2.23 mmol), N-Boc-(S)-valine (533 mg, 2.45 mmol), DCC (920 mg, 4.46 mmol), and DMAP (27 mg, 223 umol) in DCM (20 ml) was degassed and purged with N ² 3 times, and then the mixture was stirred at 15°C for 12 h under N 2 atmosphere. After filtering and concentrating under reduced pressure, the resulting residue was purified by silica gel column chromatography (petroleum ether/EtOAc = 10:1) to give ^{6 6} (1.2 g, 83%) as a pale yellow oil. 1H NMR (400 MHz, CDCh) 8.24 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 5.26 (d, J = 7.6 Hz, 1H) , 5.15 (d, J =7.6 Hz, 1H), , 4.77 (s, 4H), 4.29 (dd, J = 8.4, 4.4 Hz, 1H), 3.48 (t, J =8.4 Hz, 4H), 2.18-2.14 (m, 1H), 1.45 (s, 9H), 0.88-0.83(m, 10H), -0.02 (s, 18H). To a mixture of ⁶⁶ (200 mg, 0.301 mmol) in MeOH (10 mL) was added AcCl (49 mg, 0.62 mmol) dropwise, then the mixture was stirred at 0°C for 1 h under N2 atmosphere. The reaction mixture was concentrated under reduced pressure to give 67 (30mg, 34%) as a colorless oil which was used in the next step without further purification. 1H NMR (400 MHz, d Ms O-cC6) 8.52 (s, 2H), 7.89-7.82 (m, 2H), 7.62 (d, J = 7.6 Hz, 2H), 5.34 (s, 2H), 3.99 (s , 1H), 2.21 (s, 1H), 0.97 (d, J = 6.0 Hz, 3H), 0.94 (d, J = 6.0 Hz, 3H).

Compound 6-108 was prepared from 67 and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cfe) 9.06 (br s, 1H), 8.62 (d, J = ^{6 .8} Hz, 1H), 7.84 (d, J = 7.6 Hz, 2H), 7.60 (d, J = 7.6 Hz, 2H), 7.38-7.26 (m, 3H), 7.25 (d, J = ^{6 . 8} Hz, 1H), 5.27 (s, 2H), 4.99 (s, 2H), 4.41-4.40 (m, 1H), 2.48 (s, 3H), 2.22-2.18(m, 1H), 0.97 (d, J = 6.0 Hz, ^6H); ESI-MS m/z 461 [M+H]+; HPLC purity: 97.53% (220nm), 93.64% (254nm).

Example 109. 4-(N,N-bis(methoxymethyl)sulfamoyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate ( 6-109)

To a mixture of ^{6 6} (100 mg, 154 umol) in MeOH (10 mL) was added AcCl (24 mg, 0.31 mmol) dropwise, and then the mixture was stirred at 0°C for 1 h under N ^{2 atmosphere.} . After quenching by addition of H ² O (1 mL) at 10°C, the reaction mixture was concentrated under reduced pressure to give ^{6 8} (20 mg, 35%, colorless oil) which was used in the next step without further purification. 1H NMR (400 MHz, DMSO-cfe) 7.85 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 5.24-5.17 (m, 2H), 4.69 (s, 4H), 3.60 (t, J = 6.0 Hz, 1H). 3.13 (s, ^6H), 1.91-1.81 (m, 1H), 0.89 to 0.79 (m, ^6H).

Compound 6-109 was prepared from ^{6 8} and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-cf) 9.02 (s., 1H), 8.62 (d, J =7.2 Hz, 1H), 7.86 (d, J =8.4 Hz, 2H), 7.61 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 7.6 Hz, 1H), 5.27 (s, 2H), 4.97 (s, 2H), 4.69 (s, 4H), 4.37 (t, J = 7.2 Hz, 1H), 3.12 (s, ^6H), 2.44 (s , 3H), 2.20-2.13 (m, 1H), 0.96-.95 (m, ^6H); ESI-MS m/z 547 [M+H]+; HPLC purity: 83.51% (220nm), 83.99% (254nm).

Example 110. 3-((dimethylamino)methyl)-4-(methylsulfonyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-110)

To a solution of 61 (2.39 g, 9.99 mmol) in THF (40 mL) was added BH ³ -Me ² S (10 M, 5 mL) dropwise at 0°C under N ² . The mixture was stirred at 50°C for 12h. The reaction was quenched with water (30 mL) slowly at 0°C. The mixture was then concentrated in vacuo to remove THF. The aqueous phase was washed with EtOAc (15 mL x 2), DCM:i-PrOH = 3:1 (20 mL x 3) to remove impurities, and the aqueous phase was concentrated in vacuo to give crude 69 (2.7 g). as a white solid 1H NMR (400 MHz, DMSO-cfe) 8.42 (brs, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.71 (s, 1H), 7.61 (d, J =8.0 Hz, 1H ), 4.62 (s, 2H), 4.40 (d, J = 5.6 Hz, 2H), 3.30 (s, 3H). To a solution of 69 (1.4 g, 6.5 mmol) in MeOH (20 mL) was added a 37% aqueous HCHO solution (4.8 mL). The mixture was stirred at 15°C for 12h. NaB^CN (1.23 g, 19.5 mmol) was then added in portions at 0°C. The mixture was stirred at 15°C for 12h. The reaction was quenched with water (5 mL) slowly at 0°C, then dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo to give 70 (2 g, crude) as a yellow oil. 1H NMR (400 MHz, MeOH-d4) 8.02 (d, J = 8.0 Hz, 1H), 7.53-7.51 (m, 2H), 4.67 (s, 2H), 3.85 (s, 2H), 3.36 (s, 3H ), 2.25 (s, 6H).

Compound 6-110 was prepared from 70, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) 9.28 (s, 1H), 8.66 (d, J = 7.6 Hz, 1H), 8.09 (d, J = 8.4 Hz, 1H), 7.86 (s, 1H), 7.81 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.39-5.29 (m, 2H), 4.98 (s, 2H), 4.61 (s, 2H), 4.40 (t, J = 7.2 Hz 1H) , 3.36 (s, 3H), 2.79 (s, 6H), 2.44 (s,3H), 2.23-2.18 (m, 1H), 0.96 (d, J = 6.0 Hz, 6H).; ESI-MS m/z 517 [M+H]+; HPLC purity: 95.11% (220nm), 95.87% (254nm).

Example 111. 4-((4-Methylpiperazin-1-yl)methyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-111)

To a solution of 71 (1.8 g, 10 mmol) in DMF (15 mL) was added HATU (5.7 g, 15 mmol), TEA (3.04 g, 30 mmol), and 1-methylpiperazine (1.0 g, 10 mmol). The mixture was stirred at 15°C for 2h. The reaction mixture was partitioned between water (30 mL) and EtOAc (60 mL). The organic phase was separated, washed with brine (20 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 72 (2.1 g, 80%) as a brown oil. 1H NMR (400 MHz, DMSO-d6) 7.99 (d, J = 8.0 Hz, 2H), 7.50 (d, J = 8.4 Hz, 2H), 3.86 (s, 3H), 3.61 (s, 2H), 3.25 ( s, 2H), 2.37 (s, 2H), 2.19 (s, 2H), 1.97 (s, 3H). To a mixture of 72 (1.54 g, 5.87 mmol) in THF (20 mL) was added LiAlH ⁴ (334 mg, 8.81 mmol) at 0°C, and then the mixture was stirred at 0°C for 1 h under N atmosphere. ² . The reaction mixture was quenched by saturated potassium sodium tartrate solution (1.2 mL), filtered and concentrated under reduced pressure to give 73 (1.2 g, crude) as pale yellow oil. 1H NMR (400 MHz, DMSO-d6) 7.26-7.21 (m, 4H), 5.10 (t, J = 6.0 Hz, 1H), 4.46 (d, J = 5.6 Hz, 2H), 3.41 (s, 2H), 2.32 (s, 8H), 2.13 (s, 3H).

Compound 6-111 was prepared from 73, N-BOC-(S)-valine and acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d6) 9.05 (s, 1H), 8.61 (d, J = 7.2 Hz, 1H), 7.49 (s, 4H), 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.22 (s, 2H), 4.98 (s, 2H), 4.35 (s, 1H), 4.18 (s, 2H), 3.20 (s, 8H), 2.83 (s, 3H), 2.44 (s, 3H), 2.17 (d, J = 6.0 Hz , 1H), 0.96 (s, 6H); ESI-MS m/z 517[M+H]+; HPLC purity: 95.11% (220nm), 95.87% (254nm).

Example 112. Isopropyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-112)

Compound 6-112 was prepared in a similar manner to Example 107 using 2-bromopropane in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d6) 9.03 (s, 1H), 8.47 (d, J = 7.6 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.97-4.93 (m, 3H), 4.25 (t, J = 7.2 Hz, 1H), 2.47 (s, 3H), 2.12-2.11 (m, 1H), 1.22 (t, J = 5.6 Hz, 6H ), 0.95 (d, J = 6.4 Hz, 6H); ESI-MS m/z 334 [M+H]+; HPLC purity: 95.58% (220nm), 94.84% (254nm).

Example 113. 3-(Pyrrolidin-1-ylmethyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 113)

Compound 6-113 was prepared in a similar manner to Example 81 using pyrrolidine instead of dimethylamine. 1H NMR (400 MHz, DMSO-cfe) 9.05 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 7.55 (s, 1H), 7.50 (s, 3H), 7.34 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.22 (s, 2H), 4.97 (s, 2H), 4.38-4.32 (m, 3H), 3.33-3.23 (m, 2H), 3.09 (d, J = 6.8 Hz, 2H), 2.43 (s, 3H), 2.22-2.12 (m, 1H), 1.99 (d, J = 4.4 Hz, 2H), 1.88-1.77 (m, 2H), 0.95 ( dd, J =6.4Hz, 4.0Hz, 6H); ESI-MS m/z 465 [M+H]+; HPLC purity: 99.95% (220nm), 99.05% (254nm).

Example 114. (1-Methylpiperidin-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 114)

This compound was prepared from (1-methylpiperidin-4-yl)methanol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 10.41 (s, 1H), 9.11 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.32 (t, J = 7.2 Hz, 1H), 4.01-3.97 (m, 2H), 3.40 (d, J =11.6 Hz, 2H), 2.97-2.88 (m, 2H), 2.70 (d, J = 4.4 Hz, 3H), 2.48 (s, 3H), 2.19-2.14 (m, 1H), 1.88 (d, J =11.6 Hz, 3H), 1.56-1.50 (m, 2H), 0.98 ( d, J = 4.8 Hz, 6H); ESI-MS m/z 416 [M+H]+; HPLC purity: 99.67% (220nm), 100% (254nm).

Example 115. Cyclopentylmethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-115)

Compound 6-115 was prepared in a similar manner to Example 107 using bromomethylcyclopentane in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz , 1H), 4.97 (s, 2H), 4.30 (t, J = 7.2 Hz 1H), 4.01-3.95 (m, 2H), 2.47 (s, 3H), 2.45-2.18 (m, 2H), 1.70-1.58 (m, 2H) 1.56-1.51 (m, 4H), 1.30-1.25 (m, 2H), 0.96 (d, J = 8.0 Hz, 6H); ESI-MS m/z 374 [M+H]+; HPLC purity:

99.95% (220nm), 100% (254nm).

Example 116. Isobutyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-116)

Compound 6-116 was prepared in a similar manner to Example 107 using isobutyl bromide in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.06 (s, 1H), 8.55 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.26 (d, J =7.6 Hz , 1H), 4.99 (s, 2H), 4.33 (d, J = 7.6 Hz, 1H), 3.89 (q, J = 3.6, 2.4 Hz, 2H), 2.50 (d, J = 9.6 Hz, 3H), 2.19 2.14 (m, 1H), 1.95-1.88 (m, 1H), 0.97 (d, J = 5.2 Hz, 6H), 0.92 (d, J = 6.8 Hz, 6H); ESI-MS m/z 348 [M+H]+; HPLC purity: 99.98% (220nm), 100% (254nm).

Example 117 3-(Piperazin-1-ylmethyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 117)

A mixture of 74 (1.50 g, 4.90 mmol), N-Fmoc-(S)-valine (1.83 g, 5.39 mmol), DCC (2.02 g, 9.79 mmol), and DMAP (60 mg, 0.49 mmol) in DCM (30 ml) was degassed and purged with N ² 3 times, and then the mixture was stirred at 15°C for 12 h. After filtering and concentrating under reduced pressure, the mixture was purified by silica gel column chromatography (petroleum ether/EtOAc = 2:1) to give 75 (1.0 g, 33%) as a white solid. 1H NMR (400 MHz, CDCh) 7.77 (d, J = 7.6 Hz, 2H), 7.61 (d, J = 7.2 Hz, 2H), 7.44-7.37 (m, 2H), 735-7.27 (m, 6H), 5.19 (q, J = 12.4 Hz, 2H), 4.41 (d, J = 7.2 Hz, 2H), 4.23 (d, J = 4.8 Hz, 1H), 4.03 (s, 1H), 3.50 (s, 2H), 3.43 (s, 4H), 2.38 (s, 4H), 2.20 (d, J = 6.0 Hz, 1H), 1.50-1.44 (m, 9H), 0.97-0.92 (m, 3H), 0.88 (d, J = 6.4Hz, 3H). To a solution of 75 (1.00 g, 1.59 mmol) in THF (10 mL) was added piperidine (1.36 g, 15.9 mmol). The mixture was stirred at 15°C for 12h. The reaction mixture was diluted with H ² O (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layers were washed with brine (50 mL x 2), dried over Na ² SO ⁴ , filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (DCM/MeOH = 10/1) to give 76 (250 mg, 39%) as pale yellow oil. 1H NMR (400 MHz, DMSO-cfe) 7.38-7.22 (m, 4H), 5.20-5.02 (m, 2H), 3.47 (s, 2H), 3.30 (br s, 4H), 3.19-3.13 (m, 1H ), 2.29 (t, J = 4.4 Hz, 4H), 1.88-1.80(m, 1H), 1.38 (s, 9H), 0.86-0.78 (m, 6H). A mixture of Acid-04 (120 mg, 0.625 mmol), HATU (357 mg, 938 umol), and TEA (253 mg, 3.00 mmol) in DmF (2 mL) was stirred at 15°C for 10 min, then 76 (253 mg, 0.625 mmol) was added to the mixture and it was stirred at 15°C for 1 hour under N ² atmosphere. The reaction mixture was diluted with H ² O (10 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 77 (250 mg, crude, pale yellow oil) which was used in the following step without further purification. MS (ESI): mass calculated for C ³¹ H ⁴² BN ³ O ⁷ 579.31, m/z found 580.1 [M+H]+. To a solution of 77 (250 mg, 0.431 mmol) in EtOAc (10 mL) was added HCl/EtOAc (6 M, 1 mL). The mixture was stirred at 15°C for 2h. A little white solid then precipitated out. After filtration, the white soil was purified by preparative HPLC (column: Luna C18 100*30 5u; liquid phase: [A-HCl/H ² O = 0.040% v/v; B-ACN] B%: 5% -45%, 12 min]) to give 6-117 (93 mg, 45%) as a white solid. 1H NMR (400 MHz, DMSO-de) 9.07 (s, 1H), 8.59 (d, J = 6.0 Hz, 1H), 7.67 (s, 2H), 7.49 (s, 2H), 7.33 (s, 1H), 7.24 (s, 1H), 5.19 (s, 2H), 4.97 (s, 2H), 4.38 (s, 3H), 3.42-3.01 (m, 8H), 2.43 (s, 3H), 2.19 (s, 1H) , 0.95 (s, 6H); ESI-MS m/z 480 [M+H]+; HPLC purity: 99.91% (220nm), 100% (254nm).

Example 118. 4-Fluorobenzyl N-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-N-methyl-L-valinate (6 118)

To a mixture of 78 (2.00 g, 6.15 mmol) and NaH (492 mg, 12.30 mmol) in THF (30 mL) was added Mel (1.75 g, 12.30 mmol), then the mixture was stirred at 10°C for 12 h. in N ² atmosphere. The reaction mixture was quenched by addition of ^{saturated NH 4} Cl (60 mL) at 10°C and extracted with EtOAc (40 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 79 (400 mg, 19%) as pale yellow oil. 1H NMR (400 MHz, DMSO-d e ) 7.41 (br s, 2H), 7.20 (t, J = 8.8 Hz, 2H), 5.18-5.08 (m, 2H), 4.28 (d, J = 10.8 Hz, 1H ), 2.73 (d, J =9.2 Hz, 3H), 2.15 (m, 1H), 1.38 (s, 9H), 0.91 (brs, 3H), 0.81 (br s, 3H). To a solution of 79 (400 mg, 1.18 mmol) in EtOAc (10 mL) was added HCl/EtOAc (6 M, 1.97 mL). The mixture was stirred at 15°C for 2 hours. The reaction mixture was filtered and concentrated under reduced pressure to give 80 (300 mg, 92%) as a white solid. 1H NMR (400 MHz, CDCla) 9.63 (brs, 1H), 7.44 (dd, J = 8.4, 5.6 Hz, 2H), 7.07 (t, J = 8.4 Hz, 2H), 5.32-5.19 (m, 2H), 3.58 (d, J = 4.0 Hz, 1H), 2.72 (s, 3H), 2.60 (m, 1H), 1.13-1.06 (m, 6H).

Compound 6-118 was prepared from 80 and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 7.47 (dd, J = 8.4, 5.6 Hz, 2H), 7.30-7.19 (m, 3H), 7.06 (brs, 1H), 5.26-5.12 (m, 2H), 4.97 (s, 2H) 4.86 (brs, 1H), 3.00 (d , J = 8.4 Hz, 1H), 2.61 (s, 2H), 2.34-2.14 (m, 4H), 1.02 (d, J = 6.0 Hz, 3H), 0.93 (d, J = 6.4 Hz, 3H); ESI-MS m/z 414 [M+H]+; HPLC purity: 99.60% (220nm), 95.53% (254nm).

Example 119. Cyclohexylmethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-119)

This compound was prepared from cyclohexylmethanol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 8.52 ( d, J = 7.6 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.31 (t, J = 7.0 Hz, 1H), 3.90 (br s, 2H), 2.47 (s, 3H), 2.14 (dd, J = 12.8, 6.0 Hz, 1H), 1.78 1.56 (m, 6H), 1.29-1.01 (m, 4H ), 0.95 (d, J = 5.2 Hz, 6H); ESI-MS m/z 388 [M+H]+; HPLC urity: 99.38% (220nm), 100% (254nm).

Example 120. Thiazol-5-ylmethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-120)

Compound 6-120 was prepared in a similar manner to Example 107 using 5-(chloromethyl)thiazole in place of 2-chloroethylmethyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.13 (s, 1H), 9.02 (s, 1H), 8.57 (d, J = 7.6 Hz, 1H), 8.00 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.45 (q, J =13.2, 16.0 Hz, 2H), 4.98 (s, 2H), 4.32 (t, J = 7.2 Hz, 1H) , 2.44 (s, 3H), 2.16-2.11 (m, 1H), 0.94-0.91 (m, 6H); ESI-MS m/z 389 [M+H]+; HPLC purity: 95.91% (220nm), 94.63% (254nm).

Example 121. 4-Fluorophenethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-121)

Compound 6-121 was prepared in a similar manner to Example 107 using 1-(2-bromoethyl)-4-fluorobenzene in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-de) 9.03 (s, 1H), 8.48 (d, J = 7.2 Hz, 1H), 7.35-7.33 (m, 3H), 7.25 (d, J = 8.0 Hz, 1H), 7.11 (t, J = 8.4 Hz, 2H), 4.99 (s, 2H), 4.37-4.28 (m, 3H), 2.95-2.92 (m, 2H), 2.47 (s, 3H), 2.11-2.06 (m, 1H), 0.89 (d, J = 6.4 Hz, 6H); ESI-MS m/z414 [M+H]+; HPLC purity: 99.48% (220nm), 99.10% (254nm).

Example 122. 3-((Methylamino)methyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 122)

To a solution of tert-butyl-N-methylcarbamate (3.00 g, 22.9 mmol) in THF (50 mL) was added NaH (1.37 g, 34.3 mmol) in portions at 0°C. The reaction mixture was stirred at 15°C for one hour. Then 81 (5.24 g, 22.9 mmol) in THF (20 mL) was added dropwise. The reaction mixture was stirred at 15°C for 13h. The reaction was quenched with ice water (10 mL) slowly, then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (10 mL x 2), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 4:1) to give 82 (2.9 g, 45%) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.95-7.91 (m, 2H), 7.42-7.38 (m, 2H), 4.45 (s, 2H), 3.91 (s, 3H), 2.85 (s, 3H), 1.48 (s , 9H). To a solution of 82 (2.8 g, 10 mmol) in THF (20 mL) was added LiAlH ⁴ (456 mg, 12.0 mmol) in portions at 0°C. The mixture was stirred at 15°C for 2 hours. The mixture was cooled to 0°C and quenched with saturated sodium potassium tartrate solution (0.5 mL), the mixture concentrated in vacuo (40°C) to give 83 (1.8 g, 71%) as an oil. colorless. 1H NMR (400 MHz, CDCla) 7.32-7.29 (m, 2H), 7.27-7.23 (m, 1H), 7.15-7.14 (m, 1H), 4.68 (s, 2H), 4.42 (s, 2H), 2.82 (s, 3H), 1.48 (s, 9H). To a solution of ⁸³ (1.5 g, 6.0 mmol) in DCM (20 mL) was added N-Fmoc-(s)-valine (2.23 g, 6.57 mmol), Dc C (1.6 g, 7.8 mmol), and DMAP (73 mg, 0.60mmol). The mixture was stirred at 15°C for 12h. DCM (10 mL) was then added and the organic layer was washed with brine (10 mL x 3), dried over Na ² SO ⁴ and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 4:1) to give 84 (1.8 g, 53%) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.70-7.80 (m, 2H), 7.54-7.62 (m, 2H), 7.35-7.42 (m, 2H), 7.23-7.33 (m, 4H), 7.19 (br s, 2H ), 5.34-5.32 (m, 1H), 5.29-5.14 (m, 2H), 4.43-4.41 (m, 4H), 4.40 4.14 (m, 4H), 2.83 (s, 3H), 2.12-2.23 (m, 1H), 1.47 (s, 9H), 0.86 (dd, J = 6.84, 2.87 Hz, 6H). To a solution of 84(1.00 g, 1.75 mmol) in THF (6 mL) was added piperidine (298 mg, 3.50 mmol). The mixture was stirred at 15°C for 12h. The mixture was concentrated under reduced pressure at 40°C. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1:4) to give 85 (400 mg, 65%) as a colorless oil. 1H NMR (400 MHz, DMSO-de) 7.37-7.35 (m, 1H), 7.34-7.29 (m, 1H), 7.27-7.22 (m, 1H), 7.18-7.17 (m, 1H), 5.16-5.06 ( m, 2H), 4.37 (s, 2H), 3.15 (d, J = 4.0 Hz, 1H), ^{2.7 4} (s, 3H), 1.99-1.84 (m, 1H), 1.42-1.39 (m, 9H ), 0.85 (d, J = 6.8 Hz, 3H), 0.79 (s, J = 6.4 Hz, 3H). To a solution of Acid-04 (164 mg, 0.856 mmol) in DMF (3 mL) was added HATU (390 mg, 1.03 mmol) and TEA (260 mg, 2.57 mmol). The mixture was stirred at 20°C for 1h. Then 85 (300 mg, 0.856 mmol) was added in one portion. The mixture was stirred at 20°C for 11h. The reaction was quenched with water (10 mL) slowly at 0°C and then extracted with EtOAc (10 mL x 3). The combined organic layer was washed with brine (10 mL x 1), dried over ^{anhydrous Na 2} SO ⁴ , filtered, then HCl/EtOAc (4M, 4 mL) was added. The mixture was stirred at 20°C for 12h. The mixture was concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C18 100 x 30 mm; liquid phase: 01% TFA-ACN; B%: 10%-40%, 12 min). After preparative HPLC 3N HCl (2 mL) was added before lyophilization. 6-122(137 mg, 33%) was obtained as an off-white solid. 1H NMR (400 MHz, DMSO-de) 9.21 (brs, 2H), 9.03 (s, 1H), 8.59 (d, J = 8.0 Hz, 1H), 7.55-7.51 (m, 2H), 7.46-7.45 (m , 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.19 (s, 2H), 4.97 (s, 2H), 4.37 (t, J = 8.0 Hz 1H), 4.10 (s, 2H), 2.39 (s, 3H), 2.21-2.16 (m, 1H), 0.96 (d, J = 6.0 Hz, 6H); ESI-MS m/z 425 [M+H]+; HPLC purity: 94.93% (220nm), 87.86% (254nm).

Example 123. Quinoxalin-2-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-123)

Compound 6-123 was prepared in a similar manner to Example 107 using 2-(bromomethyl)quinoxaline in place of 2-chloroethylmethyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.05 (s, 1H), 9.01 (s, 1H), 8.63 (d, J = 8.0 Hz, 2H), 8.14-8.12 (m, 1H), 8.08-8.06 ( m, 1H), 7.90-7.88 (m, 2H), 7.36 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H), 5.57-5.49 (m, 2H), 4.96 (s , 2H), 4.46 (t, J = 4.5 Hz, 1H), 2.45 (s, 3H), 2.44-2.24 (m, 1H), 1.00 (d, J = 6.0 Hz, 6H);

ESI-MS m/z 434 [M+H]+; HPLC purity: 98.71% (220nm), 96.67% (254nm).

Example 124. Thiazol-2-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-124)

Compound 6-124 was prepared in a similar manner to Example 107 using 2-(chloromethyl)thiazole in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 7.84 (d, J = 4.0 Hz, 1H), 7.81 (d, J = 4.0 Hz , 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.52-5.41 (m, 2H), 4.97 (s, 2H), 4.38 (t, J = 8.0 Hz 1H), 2.44 (s,3H), 2.32-2.15 (m, 1H), 0.96 (d, J = 6.0 Hz, 6H); ESI-MS m/z 389 [M+H]+; HPLC purity: 99.65% (220nm), 100% (254nm).

Example 125. Quinolin-2-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-125)

Compound 6-125 was prepared in a similar manner to Example 107 using 2-(chloromethyl)quinoline in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 8.69 (d, J = 8.0 Hz, 1H), 8.64 (d, J = 8.4 Hz, 1H), 8.14-8.10 (m, 2H), 7.90 (t, J = 8.0 Hz, 1H), 7.78-7.72 (m, 2H), 7.39 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.54 (s, 2H), 4.98 (s, 2H), 4.48 (t, J = 7.2 Hz, 1H), 2.45 (s, 3H), 2.29-2.24 (m, 1H), 1.02 (d, J = 6.8 Hz, 6H); ESI-MS m/z 433 [M+H]+; HPLC purity: 97.79% (220nm), 97.66% (254nm).

Example 126. 3-(Piperazin-1-yl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-126) A mixture of 86 (3.00 g, 14.0 mmol), N-Boc-piperazine (2.73 g, 14.7 mmol), Pd(OAc) ² (313 mg, 1.40 mmol), CS ² CO ³ (9.09 g, 27.9 mmol), and BINAP (869 mg, 1.40 mmol) in toluene (20 mL) was degassed and purged with N ² 3 times, then the mixture was stirred at 100°C for 12 h under N ² atmosphere. The reaction mixture was filtered and concentrated under reduced pressure to give 87 (3.80 g, 85%) as a pale yellow solid. ¹ H NMR (400 MHz, CDCh) 7.60 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 2.4 Hz, 1H ), 3.91 (s, 3H), 3.60 (t, J = 4.4 Hz, 4H), 3.19 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). To a solution of 87 (1.00 g, 3.12 mmol) in THF (20 mL) was added LiAlH (118 mg, 3.12 mmol). The mixture was stirred at 0°C for 1h. The reaction mixture was quenched with potassium sodium tartrate (0.5 mL) at 15°C, then filtered and concentrated under reduced pressure to give 88 (700 mg, 77%) as a pale yellow oil. ¹ H NMR (400 MHz, CDCh) 7.28-7.25 (m, 1H), 6.96 (s, 1H), 6.89-6.84 (m, 2H), 4.66 (s, 2H), 3.58 (t, J = 4.8 Hz, 4H), 3.15 (t, J = 4.8 Hz, 4H), 1.49 (s, 9H). To a solution of 88 (293 mg, 1.00 mmol) and EtaN (304 mg, 3.00 mmol) in DCM (10 mL) was added MsCl (229 mg, 2.00 mmol). The mixture was stirred at 0°C for 2h. The reaction mixture was quenched by addition of H ² O (20 mL) at 15°C and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give crude 89 (200 mg, yellow solid) which was used in the next step without further purification. MS (ESI): mass calculated for C ¹⁷ H ²⁶ N ² O ⁵ S 370.16, m/z found 371.2 [M+H]+. A mixture of 89 (300 mg, 810 umol), 6-003 (236 mg, 0.810 mmol) and K ² CO ³ (336 mg, 2.43 mmol) in DMF (5 mL) was stirred at 60 °C for 1 h in N ² atmosphere. The reaction mixture was quenched with H ² O (10 mL) at 15°C and then extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (10 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give crude 90 (400 mg, pale yellow oil) which was used in the next step. without further purification. MS (ESI): mass calculated for C ³⁰ H ⁴⁰ BN ³ O ⁷ 565.30, m/z found 566.3 [M+H]+. To a solution of 90 (400 mg, 0.707 mmol) in EtOAc (10 mL) was added HCl/EtOAc (6 M, 1.18 mL). The mixture was stirred at 15°C for 1h. After concentrating under reduced pressure, the reaction mixture was purified by preparative HPLC (column: Luna C18 100 x 30 mm; liquid phase: [A-HCl/H ² O = 0.040% v/v; B-ACN] B% :13%-43%, 12 min]) to give 6-126 (102 mg, 28%) as a white solid. ¹ H NMR (400 MHz, DMSO-d e ) 9.17 (s, 2H), 8.58 (d, J = 7.2 Hz, 1H), 7.34 (d, J =7.2 Hz, 1H), 7.28-7.22 (m, 2H ), 7.01 (s, 1H), 6.95 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 7.2 Hz, 1H), 5.13 (s, 2H), 4.97 (s, 2H), 4.34 (t , J = 7.2 Hz, 1H), 3.36 (d, J = 5.2 Hz, 4H), 3.17 (d, J = 2.8 Hz, 4H), 2.44 (s, 3H), 2.20-2.11 (m, 6.8 Hz, 1H ), 0.958-0.942 (m, 6H); ESI-MS m/z 466 [M+H]+; HPLC purity: 97.27% (220nm), 96.92% (254nm).

Example 127. Quinolin-6-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-127)

Compound 6-127 was prepared in a similar manner to Example 107 using 6-(chloromethyl)quinoline in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.00 (s, 1H), 8.88 (d, J = 3.2 Hz, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.32 (d, J = 3.2 Hz , 1H), 8.02-8.00 (m, 2H), 7.55-7.52 (m, 1H), 7.33-7.31 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.18 (d, J =8.0 Hz, 1H), 5.37-5.36 (m, 2H), 4.94 (s, 2H), 4.38 (t, J = 7.2 Hz, 1H), 2.41 (s, 3H), 2.18-2.14 (m, 1H), 0.93 (d, J =6.4Hz, 6H); ESI-MS m/z 433 [M+H]+; HPLC purity: 99.81% (220nm), 100% (254nm).

Example 128. Thiazol-4-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-128)

Compound 6-128 was prepared in a similar manner to Example 107 using 4-(chloromethyl)thiazole in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.09 (s, 1H), 9.02 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.75 (d, J =1.2 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 5.30-5.21 (m, 2H), 4.94 (s, 2H), 4.32 (t, J = 7.6 Hz, 1H) , 2.41 (s, 3H), 2.14-2.09 (m, 1H), 0.91 (dd, J = 4.0 Hz, 2.8 Hz, 6H); ESI-MS m/z 389 [M+H]+; HPLC purity: 99.53% (220nm), 100% (254nm).

Example 129. 4-Fluorobenzyl(1-hydroxy-5-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-129)

This compound was prepared from 4-fluorobenzyl alcohol, N-BOC-(S)-valine, and Acid-14 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-de) 9.19 (s, 1H), 8.60 (d, J = 7.6 Hz, 1H), 7.66 (s, 1H), 7.46-7.42 (m, 2H), 7.24 (s, 1H), 7.19 (d, J =8.8 Hz, 1H), 5.14 (q , J =12.4, 5.6 Hz, 2H), 4.95 (s, 2H), 4.33 (t, J = 6.8 Hz, 1H), 2.30 (s, 3H), 2.16 2.11 (m, 1H), 0.91 (d, J = 6.4Hz, 6H); ESI-MS m/z 400 [M+H]+; HPLC purity: 99.53% (220nm), 100% (254nm).

Example 130. 4-(Morpholinomethyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-130)

This compound was prepared from (4-(morpholinomethyl)phenyl)methanol, N-BOC-(S)-valine and Acid-14 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-de) 9.06 ( br s, 1H), 8.62 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 7.2 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.2 Hz , 1H), 7.25 (d, J = 7.2 Hz, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 4.35 (s, 3H), 3.94 (d, J = 11.6 Hz, 2H), 3.75 (t, J =11.2 Hz, 2H), 3.21 (d, J = 10.4 Hz, 2H), 3.10 (s, 2H), 2.44 (s, 3H), 2.18 (d, J = 6.0 Hz, 1H), 0.97 (s, 6H); ESI-MS m/z 481 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 131 4-(Pyrrolidin-1-ylmethyl)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 131)

To a solution of 91 (3.0 g, 13 mmol) and pyrrolidine (1.21 g, 17.0 mmol) in CH ³ CN (10 mL) was added K ² CO ³ (5.43 g, 39.0 mmol). The mixture was stirred at 80°C for 12h. After filtering, the residue was washed with CH3CN (3 mL), and the combined filtrate was concentrated under reduced pressure to give 92 (2.5 g, 87%) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.97 (d, J =7.6 Hz, 2H), 7.39 (d, J =8.0 Hz, 2H), 3.90 (s, 3H), 3.65 (s, 2H), 2.50 (s, 4H), 1.78 (s, 4H). To a solution of 92 (0.80 g, 3.6 mmol) in THF (50 mL) was added LiAlH ⁴ (208 mg, 5.00 mmol) in portions at 0°C, and then the mixture was stirred at 20°C for 12 h. The reaction mixture was quenched with saturated potassium sodium tartrate (1 mL) at 0°C and then filtered. The filtrate was concentrated under reduced pressure to give 93 (0.51 g, crude) as a colorless oil. 1H NMR (400 MHz, CDCh) 7.39-7.32 (m, 4H), 4.70 (s, 2H), 3.63 (s, 2H), 2.52 (s, 4H), 1.82-1.79 (m, 4H).

Compound 6-131 was prepared from 93, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-de) 10.05 (s, 1H), 9.07 (s, 1H), 8.62 (d, J = 7.6 Hz, 1H), 7.56 (d, J =8.0 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H), 7.36 (d, J =8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 5.23 (s, 2H), 4.98 (s, 2H), 4.38-4.35 (m, 3H), 3.35 (s, 2H), 3.18-3.06 (m, 2H), 2.44 (s, 3H), 2.21-2.15 (m, 1H), 2.04 (m, 2H), 1.89-1.86 (m, 2H), 0.98-0.95 (m, 6H); ESI-MS m/z 465 [M+H]+; HPLC purity: 95.74% (220nm), 92.57% (254nm).

Example 132. Cyclopentyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-132)

Compound 6-132 was prepared in a similar manner to Example 107 using bromocyclopentane in place of 2-chloroethylmethyl ether. 1H NMR (400 MHz, DMSO-d e ) 8.96 (s, 1H), 8.49 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.6 Hz, 1H), 7.26 (d, J = 7.6 Hz , 1H), 5.15 (s, 1H), 4.99 (s, 2H), 4.27 (t, J = 7.2 Hz, 1H), 2.51 (s, 3H), 2.18-2.10 (m, 1H), 1.85 (d, J = 4.8 Hz, 2H), 1.68-1.58 (m, 6H), 0.96 (d, J = 6.4 Hz, 6H); ESI-MS m/z 360 [M+H]+; HPLC purity: 99.59% (220nm), 97.74% (254nm).

Example 133. Cidohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-133)

Compound 6-133 was prepared in a similar manner to Example 107 using bromocyclohexane in place of 2-chloroethyl methyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 8.48 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz , 1H), 4.97 (s, 2H), 4.75 (s, 1H), 4.28 (t, J = 6.0 Hz 1H), 2.48 (s, 3H), 2.15-2.13 (m, 1H), 1.78 (s, 2H ), 1.68 (s, 2H), 1.45-1.31 (m, 6H), 0.95 (d, J = 4.0 Hz, 6H); ESI-MS m/z 374 [M+H]+; HPLC purity: 99.57% (220nm), 100% (254nm).

Example 134. Tetrahydro-2H-pyran-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-134)

This compound was prepared from tetrahydro-2H-pyran-4-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.97-4.94 (m, 3H) , 4.29 (t, J = 8.0 Hz 1H), 3.82-3.78 (m, 2H), 3.49-3.36 (m, 2H), 2.48 (s, 3H), 2.18-2.13 (m, 1H), 1.88-1.85 ( m, 2H), 1.57-1.53 (m, 2H), 0.96 (d, J = 4.0 Hz, 6H); ESI-MS m/z 376 [M+H]+; HPLC purity: 98.56% (220nm), 98.51% (254nm).

Example 135 Oxetan-3-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-135)

This compound was prepared from oxetan-3-ol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1.

1H NMR (400 MHz, DMSO-d e ) 9.05 (s, 1H), 8.62 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz , 1H), 5.46-5.43 (m, 1H), 4.98 (s, 2H), 4.83 (t, J = 8.0 Hz, 2H), 4.52-4.47 (m, 2H), 4.32 (t, J = 4.0 Hz, 1H), 2.32 (s, 3H), 2.20 2.15 (m, 1H), 0.99 (dd, J = 4.0 Hz, 8.0 Hz, 6H); ESI-MS m/z 348 [M+H]+; HPLC purity: 95.11% (220nm), 96.76% (254nm).

Example 136. Cyclobutyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-136)

This compound was prepared from cyclobutanol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.05 (br s, 1H), 8.51 ( d, J = 7.2 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 4.97-4.92 (m, 3H), 4.25 (t, J = 7.2 Hz, 1H), 2.48 (s, 3H), 2.30 (d, J = ^8.8 Hz, 2H), 2.14-2.12 (m, 1H), 2.07-2.00 (m, 2H), 1.76 (q, J = 10.0 Hz, 1H), 1.63-1.58 (m, 1H), 0.95 (d, J = 6.4 Hz, ⁶ H); ESI-MS m/z 346 [M+H]+; HPLC purity: 99.96% (220nm), 100% (254nm).

Example 137 Quinazolin-2-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-137)

A mixture of 94 (5.00 g, 26.9 mmol), acetamidine (3.12 g, 53.8 mmol), CuBr (385 mg, 2.69 mmol), and K ² CO ³ (11.1 g, 80.6 mmol) in DMSO (50 mL) was degassed and purged with N ² 3 times, and then the mixture was stirred at 100°C for 14 h under N ² atmosphere and then under air for 2 h at 25°C. The reaction was quenched with water (50 mL) slowly, then extracted with EtoAc (40 mL x 3). The combined organic phase was washed with brine ⁽²⁰ mL x ² ), dried over ^{anhydrous Na 2} SO ⁴ , filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 5:1) to give 95 (2.5 g, 65%) as a yellow oil. 1H NMR (400 MHz, CDCla) 9.33 (s, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.90-7.86 (m, 2H) 7.60 (t, J = 8.0 Hz, 1H), 2.91 (s , 3H). To a solution of 95 (1.40 g, 9.71 mmol) in CCl ⁴ (10 mL) was added NBS (1.56 g, 8.74 mmol) and BPO (470 mg, 1.94 mmol). The mixture was stirred at 80°C for 2h. The reaction was filtered and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether/ethyl acetate = 4:1) to give 96 (150 mg, 6.9%) as a yellow solid. 1H NMR (400 MHz, CDCla) 9.46 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.98-7.95 (m, 2H) 7.70 (t, J = 8.0 Hz, 1H), 4.80 (s , 2H).

Compound 6-137 was prepared in a similar manner to Example 107 using 96 in place of 2-chloroethylmethyl ether. 1H NMR (400 MHz, DMSO-d e ) 9.63 (s, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H), 8.03 (t, J = 4.0 Hz , 1H), 7.94 (d, J = 8.0 Hz, 1H), 7.77 (t, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H ), 5.54 (d, J =16.0 Hz, 1H), 5.43 (d, J =16.0 Hz, 1H), 4.97 (s, 2H), 4.53 (t, J =8.0 Hz 1H), 2.47 (s, 3H) , 2.38-2.33 (m, 1H), 1.08 (d, J =8.0 Hz, ⁶ H); ESI-MS m/z 434 [M+H]+; HPLC purity: 97.45% (220nm), 95.68% (254nm).

Example 138. (1H-imidazol-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-138)

To a solution of 97 (3.00 g, 23.8 mmol) in DMF (5 mL) was added NaH (1.14 g, 28.6 mmol) in portions at 0°C. The mixture was stirred at 0°C for 1h. SEM-Cl (8.44 mL, 47.6 mmol) was then added dropwise at 0°C. The reaction mixture was stirred at 25°C for 13h. The reaction was quenched by ^{saturated aqueous NH 4} Cl (10 mL) at 0°C and then extracted with EtOAc (20 mL x 3). The combined organic phase was washed with brine (20 mL), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 1:2) to give 98 (2.00 g, 33% yield) as a yellow oil. 1H NMR (400 MHz, CDCh) 7.73 (s, 1H), 7.62 (s, 1H), 5.31 (s, 2H), 3.91 (s, 3H), 3.50 (t, J = 8.0 Hz, 2H), 0.92 ( t, J = 8.0 Hz, 2H), -0.01 (s, 9H). To a solution of 98 (2.00 g, 7.80 mmol) in THF (20 mL) was added LiAlH ⁴ (355 mg, 9.36 mmol) in portions at 0°C. The mixture was stirred at 25°C for 3h. The reaction was quenched by saturated aqueous potassium sodium tartrate (1 mL) at 0°C, filtered and concentrated in vacuo to give 99 (1.4 g, 79% yield) as a colorless oil.

1H NMR (400 MHz, CDCh) 7.56 (s, 1H), 6.99 (s, 1H), 5.23 (s, 2H), 4.61 (s, 2H), 3.48 (t, J =8.0 Hz, 2H), 0.91 ( t, J = 8.0 Hz, 2H), 0.01 (s, 9H).

Compound 6-138 was prepared from 99 and Acid-04 in a similar manner to Example 108. 1H NMR (400 MHz, DMSO-d e ) 9.15 (s, 1H), 8.60 (d, J = 8.0 Hz, 1H), 7.75 (s, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 5.28 (d, J = 12.0 Hz, 1H), 5.18 (d, J = 12.0 Hz, 1H), 4.96 (s, 2H), 4.33 (t, J = 8.0 Hz 1H), 2.47 (s, 3H), 2.18-2.13 (m, 1H), 0.92 (dd, J = 4.0 Hz , 8.0 Hz, ⁶ H); ESI-MS m/z 372 [M+H]+; HPLC purity: 96.31% (220nm), 99.54% (254nm).

Example 139. 1,3-Dimethoxypropan-2-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-139)

This compound was prepared from 1,3-dimethoxypropan-2-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.03 ( s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.12-5.09 (m, 1H), 4.97 (s, 2H), 4.35-4.31 (m, 1H), 3.51-3.46 (m, 4H), 3.25 (d, J =10.0 Hz, 6H), 2.47 (s, 3H), 2.17-2.12 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H); ESI-MS m/z 394 [M+H]+; HPLC purity: 99.79% (220nm), 100% (254nm).

Example 140. (S)-Tetrahydrofuran-3-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-140)

This compound was prepared from (S)-tetrahydrofuran-3-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.04 ( br s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.2 Hz, 1H) 7.25 (d, J = 7.6 Hz, 1H), 5.29 (s, 1H), 4.98 ( s, 2H), 4.26 (t, J = 6.8 Hz, 1H), 3.84-3.67 (m, 4H), 2.48 (s, 3H) 2.21-2.13 (m, 2H), 1.94 1.92 (m, 1H), 0.96 (d, J = 6.4Hz, 6H); ESI-MS m/z 362 [M+H]+; HPLC purity: 99.71% (220nm), 98.22% (254nm).

Example 141. (R)-Tetrahydrofuran-3-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-141)

This compound was prepared from (R)-tetrahydrofuran-3-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.05 (br s, 1H), 8.54 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H) 7.25 (d, J = 8.0 Hz, 1H), 5.29 (t, J = 5.2 Hz , 1H)4.97 (s, 2H), 4.26 (t, J = 7.2 Hz, 1H), 3.81-3.72 (m, 4H), 2.47 (s, 3H), 2.19-2.11 (m, 2H), 1.91-1.88 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H); ESI-MS m/z 362 [M+H]+; HPLC purity: 99.83% (220nm), 100% (254nm).

Example 142. 1-Methylpiperidin-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-142)

This compound was prepared from 1-methylpiperidin-4-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-de) 10.85 (s, 1H ), 9.10 (s, 1H), 8.59 (d, J = 7.2 Hz, 1H), 7.38 (t, J = 7.2 Hz, 1H), 7.49 (q, J = 2.8 Hz, 4.8 Hz, 1H), 4.99 ( s, 2H), 5.10-4.92 (m, 1H), 4.43-4.24 (m, 1H), 3.43 (d, J =12.4 Hz, 1H), 3.34 (s, 1H), 3.113.08 (m, 2H), 2.74-2.71 (m, 3H), 2.49 (s, 3H), 2.15-2.14 (m, 1H), 2.12-1.94 (m, 4H), 0.98 (t, J = 6.0 Hz, 6H); ESI-MS m/z 389 [M+H]+; HPLC purity: 97.80% (220nm), 96.87% (254nm).

Example 143. (1H-imidazol-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-143)

This compound was prepared from methyl 1H-imidazole-2-carboxylate and Acid-04 in a similar manner to Example 138. 1H NMR (400 MHz, DMSO-d e ) 9.00 (brs, 1H), 8.67 (d, J =6.8 Hz, 1H), 7.73 (s, 2H), 7.36 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.2 Hz, 1H), 5.42 (s, 2H), 4.97 (s, 2H), 4.41 (t, J = 6.8 Hz, 1H), 2.42 (s, 3H), 2.23-2.18 (m, 1H), 0.94 (d, J = 6.8 Hz, 6H); ESI-MS m/z 372 [M+H]+; HPLC purity: 93.06% (220nm), 90.56% (254nm).

Example 144. ((R)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6 -carbonyl)-L-valinate (6-144)

This compound was prepared from (S)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.03 (s, 1H), 8.54 (d, J =7.6 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz , 1H), 4.99 (s, 2H), 4.34 (t, J = 7.6 Hz, 1H), 4.30-4.27 (m, 1H), 4.26-4.20 (m, 1H), 4.11-4.02 (m, 2H), 3.71 (t, J = 7.2 Hz, 1H), 2.49 (s, 3H), 2.19-2.13 (m, 1H), 1.35 (s, 3H), 1.29 (s, 3H), 0.98 (d, J = 6.8 Hz , 6H); ESI-MS m/z 406 [M+H]+; HPLC purity: 98.83% (220nm), 99.07% (254nm).

Example 145. ((S)-2,2-Dimethyl-1,3-dioxolan-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6 -carbonyl)-L-valinate (6-145)

This compound was prepared from (R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 9.03 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz , 1H), 4.98 (s, 2H), 4.32-4.29 (m, 2H), 4.15-4.12 (m, 2H), 4.10-4.02 (m, 1H), 3.71-3.69 (m, 1H), 2.47 (s , 3H), 2.18-2.13 (m, 1H), 1.34 (s, 3H), 1.28 (s, 3H), 0.96 (d, J = 8.0 Hz, 6H); ESI-MS m/z 406 [M+H]+; HPLC purity: 98.83% (220nm), 99.07% (254nm).

Example 146 Piperidin-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-146) This compound was prepared from tert-butyl 4-hydroxypiperidine-1-carboxylate, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117. 1H NMR (400 MHz, DMSO-ecf) 8.96 (s, 2H), 8.60 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 5.03-4.99 (m, 1H ), 4.98 (s, 2H), 4.30 (t, J = 8.0 Hz, 1H), 3.20-3.17 (m, 2H), 3.10 3.08 (m, 2H), 2.48 (s, 3H), 2.17-2.15 (m , 1H), 2.02-2.00 (m, 2H), 1.82-1.80 (m, 2H), 0.96 (d, J = 8.0 Hz, 6H); ESI-MS m/z 375 [M+H]+; HPLC purity: 98.56% (220nm), 96.69% (254nm).

Example 147. (R)-2,3-dihydroxypropyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-147)

A mixture of 6-144 and 37% HCl (0.5 mL) in DMF (5 mL) was stirred at 25°C for another 12 h. The mixture was filtered and concentrated in vacuo. The residue was purified by preparative HPLC (column: Luna C8 100 x 30 mm; liquid phase: water water (0.1% TFA)-ACN; B%:10%-35%, 12 min) to give 6-147 (206 mg , 3%) as a white solid. 1H NMR (400 MHz, DMSO-cfe) 9.01 (s, 1H), 8.45 (d, J = 8.0 Hz, 1H), 7.34 (d, J = 7.6 Hz, 1H), 7.20 (d, J = 8.0 Hz, 1H), 4.94 (s, 2H), 4.83-4.75 (m, 1H), 4.64 (s, 1H), 4.34 (t, J = 7.2 Hz, 1H), 4.14-4.10 (m, 1H), 3.95-3.92 (m, 1H), 3.65-3.63 (m, 1H), 3.47 3.34 (m, 2H), 2.44 (s, 3H), 2.17-2.09 (m, 1H), 0.92 (t, J = 4.4 Hz, 6H) ; ESI-MS m/z 366 [M+H]+; HPLC purity: 98.56% (220nm), 96.69% (254nm).

Example 148. (S)-2,3-dihydroxypropyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-148)

This compound was prepared from 6-145 in a similar manner to Example 147. 1H NMR (400 MHz, DMSO-cf) 9.02 (s, 1H), 8.47 (d, J = 8.0 Hz, 1H), 7.38 (d , J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.39-4.36 (m, 1H), 4.23-4.13 (m, 1H), 4.03-3.99 ( m, 1H), 3.69-3.65 (m, 2H), 3.39-3.37 (m, 2H), 2.48 (s, 3H), 2.38-2.33 (m, 1H), 0.97-0.95 (m, 6H); ESI-MS m/z 366 [M+H]+; HPLC purity: 99.66% (220nm), 99.63% (254nm).

Example 149. 3-Hydroxy-2-(hydroxymethyl)propyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-149)

To a solution of 100 (1.06 g, 12.0 mmol) in DCM (20 mL) was added N-Boc-(S)-valine (2.17 g, 9.99 mmol), DCC (2.68 g, 13.0 mmol), and DMAp. (122mg, 0.999mmol). The mixture was stirred at 25°C for 14h. The mixture was filtered and concentrated in vacuo. The residue was purified by column chromatography (petroleum ether/ethyl acetate = 5:1) to give 101 (2.1 g, 73%) as a colorless oil. 1H NMR (400 MHz, CDCfe) 4.99-4.83 (m, 1H), 4.81-4.80 (m, 2H), 4.48-4.46 (m, 2H), 4.40-4.37 (m, 2H), 4.14-4.12 (m, 1H), 3.36-3.29 (m, 1H), 2.14-2.11 (m, 1H), 1.45 (s, 9H), 0.97 (d, J = 8.0 Hz, 3h), 0.90 (d, J = 8.0 Hz, 3H ). To a solution of 101 (1.00 g, 3.48 mmol) in DCM (15 mL) was added TFA (5 mL). The mixture was stirred at 25°C for 2h. The mixture was concentrated in vacuo to give 102 (800 mg, 76%) as a colorless oil. 1H NMR (400 MHz, CDCla) 4.40-4.55 (m, 1H), 4.24-4.33 (m, 1H), 3.95-4.03 (m, 1H), 3.73-3.86 (m, 1H), 2.32-2.44 (m, 1H), 1.08 (t, J = 7.5 Hz, 6H). To a solution of Acid-04 (200 mg, 1.04 mmol) in DMF (3 mL) was added HATU (474 mg, 1.25 mmol) and NMM (315 mg, 3.12 mmol). The mixture was stirred at 25°C for 0.5h. then added 102 (344 mg, 1.14 mmol) in one serving. The mixture was stirred at 25°C for 12h. The mixture was purified by preparative HPLC (column: Luna C8100 x 30 mm; liquid phase: water (0.1% TFA)-ACN; B%:18%-48%, 12 min) to give 6-149 (101 mg, 26 %) as a white solid. 1H NMR (400 MHz, DMSO-d e ) 9.04 (s, 1H), 8.51 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz , 1H), 4.97 (s, 2H), 4.51 (t, J = 4.0 Hz, 2H), 4.32 (t, J = 8.0 Hz 1H), 4.10 4.05 (m, 2H), 3.47-3.42 (m, 4H) , 2.47 (s, 3H), 1.88-1.85 (m, 1H), 2.23-2.21 (m, 1H), 0.95 (d, J = 8.0 Hz, 6H); ESI-MS m/z 380 [M+H]+; HPLC purity: 99.75% (220nm), 100% (254nm).

Example 150 Oxetan-3-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-150)

This compound was prepared from oxetan-3-ylmethanol, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117. 1H NMR (400 MHz, DMSO-d e ) 9.05 (s, 1H) , 8.55 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H), 4.64-4.38 (m, 2H), 4.37-4.30 (m, 5H), 3.30-3.27 (m, 1H), 2.47 (s, 3H), 2.17-2.12 (m, 1H), 0.96 (dd, J = 4.0 Hz, 8.0 Hz, 6H ); ESI-MS m/z 362 [M+H]+; HPLC purity: 96.41% (220nm), 97.05% (254nm).

Example 151. 2,2,2-trifluoroethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-151)

This compound was prepared from 2,2,2-trifluoroethane-1-ol, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117. 1H NMR (400 MHz, DMSO-d e ) 9.05 (s, 1H), 8.55 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.98 (s, 2H) , 4.64-4.38 (m, 2H), 4.37-4.30 (m, 5H), 3.30-3.27 (m, 1H), 2.47 (s, 3H), 2.17-2.12 (m, 1H), 0.96 (dd, J = 4.0Hz, 8.0Hz, 6H); ESI-MS m/z 362 [M+H]+; HPLC purity: 96.41% (220nm), 97.05% (254nm).

Example 152. (4-(methoxymethyl)tetrahydro-2H-pyran-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L -valinate (6-152)

To a solution of 103 (5.00 g, 34.7 mmol) in THF (50 mL) was added LDA (2 M, 17.3 mL) at -78°C. The mixture was stirred at 0°C for 0.5h. MOMCI (4.19 g, 52.0 mmol) was then added in one portion at -78°C. The mixture was stirred at 25°C for 1h. The reaction was quenched with water (20 mL) slowly, then extracted with EtOAc (20 mL x 3). The combined organic layer was washed with brine (20 mL), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo to give 104 (5.6 g, crude) as a yellow oil. 1H NMR (400 MHz, CDCh) 3.76-3.69 (m, 2H), 3.67 (s, 3H), 3.42 3.40 (m, 2H), 3.39 (s, 2H), 3.24 (s, 3H), 2.01-1.98 ( m, 2H), 1.55-1.48 (m, 2H). To a solution of 104 (2.00 g, 10.6 mmol) in THF (20 mL) was added LiAlH ⁴ (807 mg, 21.3 mmol) in portions at 0°C. The mixture was stirred at 25°C for 12 hours. The mixture was cooled to 0°C and quenched with saturated sodium potassium tartrate solution (3 mL), the precipitate formed was collected, filtered and concentrated in vacuo to give crude 105 (1.2 g) as a solid. colorless oil and used stepwise without further purification. 1H NMR (400 MHz, CDCla) 3.67-3.64 (m, 6H), 3.40 (s, 2H), 3.35 (s, 3H), 1.53-1.48 (m, 4H).

Compound 6-152 was prepared from 105, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117.

1H NMR (400 MHz, DMSO-de) 9.04 (s, 1H), 8.54 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.97 (s, 2H), 4.34 (t, J = 8.0 Hz, 1H), 4.04 (q, J = 8.0 Hz, 2H), 3.56 (t, J = 8.0 Hz, 4H), 3.30 (s, 2H), 3.24 (s, 2H), 2.47 (s, 3H), 2.16-2.13 (m, 1H), 1.45 (s, 4H), 0.96 (d, J = 8.0 Hz, 6H); ESI-MS m/z 434 [M+H]+; HPLC purity: 97.28% (220nm), 97.90% (254nm).

Example 153

This compound was prepared from 2,2,3,3,3-pentafluoropropan-1-ol, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117. 1H NMR (400 MHz, DMSO-d e ) 9.05 (s, 1H), 8.68 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J =8.0 Hz, 1H), 4.98 ( s, 2H), 4.93-4.82 (m, 2H), 4.40 (t, J = 7.2 Hz, 1H), 2.47 (s, 3H), 2.20-2.13 (m, 1H), 0.98 (dd, J = 6.4 Hz 2.4Hz, 6H); ESI-MS m/z 424 [M+H]+; HPLC purity: 99.71% (220nm), 100% (254nm).

Example 154. (4,4-Difluorocidohexyl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 154)

To a solution of 106 (4.00 g, 20.8 mmol) in THF (40 mL) was added LiAlH ⁴ (1.18 g, 31.2 mmol) in portions at 0°C. The mixture was stirred at 25°C for 4h. The mixture was cooled to 0°C and quenched with saturated sodium potassium tartrate solution (3 mL), the precipitate formed was collected, filtered and concentrated in vacuo to give 107 (2.6 g, 83%) as a colorless oil. 1H NMR (400 MHz, CDCla) 3.45 (J = 4.0 Hz, 2H), 2.07-2.03 (m, 2H), 2.01-1.83 (m, 2H), 1.82 1.79 (m, 2H), 1.72-1.64 (m, 1H), 1.28-1.24 (m, 2H).

Compound 6-154 was prepared from 107, N-Fmoc-(S)-valine and Acid-04 in a similar manner to Example 117.

1H NMR (400 MHz, DMSO-d e ) 9.03 (s, 1H), 8.53 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz , 1H), 4.97 (s, 2H), 4.31 (t, J = 8.0 Hz, 1H), 3.99 (d, J = 8.0 Hz, 2H), 2.47 (s, 3H), 2.17-2.11 (m, 1H) , 2.07-2.01 (m, 2H), 1.85 1.79 (m, 5H), 1.28-1.25 (m, 2H), 0.98 (d, J = 4.0 Hz, 3H), 0.94 (d, J = 4.0 Hz, 3H) ; ESI-MS m/z 424 [M+H]+; HPLC purity: 96.95% (220nm).

Example 155. 4,4-Difluorocyclohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-155)

This compound was prepared from 4,4-difluorocyclohexan-1-ol, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117. 1H NMR (400 MHz, DMSO-d e ) 9.04 ( s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 1H), 4.97 (s, 3H), 4.30 ( t, J = 8.0 Hz, 1H), 2.47 (s, 3H), 2.16-2.13 (m, 1H), 2.07-1.99 (m, 4H), 1.85-1.76 (m, 4H), 0.96 (d, J = 8.0Hz, 6H); ESI-MS m/z 410 [M+H]+; HPLC purity: 99.28% (220nm), 99.20% (254nm).

Example 156. 1,1,1,3,3,3-Hexafluoropropan-2-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L -valinate (6-156)

This compound was prepared from 1,1,1,3,3,3-hexafluoropropan-2-ol, N-Fmoc-(S)-valine and Acid-04 in a similar manner to Example 117. 1H NMR (400 MHz, DMSO-de) 9.06 (s, 1H), 8.84 (d, J = 8.0 Hz, 1H), 7.36 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.93 -6.86 (m, 1H), 4.98 (s, 2H), 4.42 (t, J = 8.0 Hz, 1H), 2.49 (s, 3H), 2.20-2.07 (m, 1H), 1.00 (q, J = 8.0 Hz, 6H); ESI-MS m/z 442 [M+H]+; HPLC purity: 96.04% (220nm), 93.40% (254nm).

Example 157. (1,4-dioxepan-6-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6- 157)

A mixture of ethylene glycol (6.46 g, 104 mmol) and NaH (10.4 g, 260 mmol, 60% purity) in DMF (50 mL) was stirred at 0 °C for 0.5 h. 108 (13.00 g, 104 mmol) was then added to the mixture and stirred at 15°C for 2.5 h. The reaction mixture was diluted with H ² O (100 mL) and extracted with MTBE (50 mL x 2). The combined organic layers were washed with brine (30 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 109 (8.0 g, crude yellow oil) for use in the next step without purification. additional.

To a solution of 109 (8.00 g, 70.1 mmol) in THF (50 mL) was added BH ³ -Me ² S (10 M, 7.7 mL). The mixture was stirred at 0°C for 1h. ^{Then H 2} O ² (23.8 g, 210 mmol, 30% purity) was added dropwise to the reaction mixture, aqueous NaOH (1 M, 210 mL) was added under ice-cooling, and the mixture was stirred at 0°C. C for 1 h. The mixture was extracted with DCM/isopropanol (6/1.50 mL x 2). The organic layer was washed with saturated brine (50 ml) and dried over Na ² SO ⁴ and the solvent evaporated under reduced pressure to give 110 (120 g, crude) as a pale yellow oil.

Compound 6-157 was prepared from 110, N-Fmoc-(S)-valine and Acid-04 in a similar manner to Example 117.

1H NMR (400 MHz, DMSO-de) 8.53 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J =8.0 Hz, 1H), 4.97 (s, 2H), 4.30 (t, J = 7.2 Hz, 1H), 4.05-4.03 (m, 2H), 3.82 (dd, J = 12.4, 5.2 Hz, 2H), 3.64-3.61 (m, 6H), 2.47 (s , 3H), 2.31-2.28 (m, 1H), 2.18-2.11 (m, 1H), 0.95 (dd, J = 6.8, 2.4 Hz, 6H); ESI-MS m/z 406 [M+H]+; HPLC purity: 99.36% (220nm), 99.47% (254nm).

Example 158. (3-(methoxymethyl)oxetan-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -158)

A mixture of 111 (100 g, 734 mmol), diethyl carbonate (104 g, 881 mmol), and KOH (412 mg, 7.34 mmol) in EtOH (25 mL) was degassed and purged with N ² 3 times, then the mixture was stirred at 140°C for 12 h under N ² atmosphere. After distilling off EtOH and diethyl carbonate, the mixture was purified by distillation under reduced pressure (0.019 mbar) to give 112 (20.0 g, 23%) as a white gum. 1H NMR (400 MHz, DMSO-cfe) 4.76 (br s, 1H), 4.27 (s, 4H), 3.54 (s, 4H). To a solution of 112 (5.00 g, 42.3 mmol) and NaOH (1.69 g, 42.3 mmol) in DMF (20 mL) was added Mel (5.41 g, 38.1 mmol) dropwise at 0°C. The mixture was stirred at 15°C for 12h. DMF was evaporated under reduced pressure, the reaction mixture was diluted with H ² O (50 mL) and extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give 113 (1.00 g, crude, brown oil) for use in the next step without purification. additional.

Compound 6-158 was prepared from 113, N-Fmoc-(S)-valine, and Acid-04 in a similar manner to Example 117.

1H NMR (400 MHz, DMSO-de) 9.04 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.37 (d, J = 8.0 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1 HOUR), 4.97 (s, 2H), 4.39-4.33 (m, 5H), 4.28 (s, 2H), 3.56 (s, 2H), 3.30 (s, 3H), 2.47 (s, 3H), 2.20-2.12 (m, 1H), 0.96 (d, J = 6.4 Hz, 6H); ESI-MS m/z 406 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 159. (2-(trifluoromethyl)pyrimidin-5-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -159)

To a solution of 114 (500 mg, 2.84 mmol) in THF (10 mL) was added BH ³ -Me ² S (10 M, 2.84 mL) at 0°C. The mixture was stirred at 0°C for 5h. The reaction mixture was quenched by the addition of MeOH (5 mL) at 0°C, then concentrated under reduced pressure to give a residue. Crude 115 (500 mg, white solid) was used in the next step for further purification.

Compound 6-159 was prepared from 115, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1.1H NMR (400 MHz, DMSO-d e ) 9.14 (s, 2H), 9.05 (brs, 1H), 8.66 (d, J= 7.6 Hz, 1H), 7.36 (d, J = 7.2 Hz, 1H), 7.25 (d, J = 7.6 Hz, 1H), 5.42-5.36 (m, 2H ), 4.98 (s, 2H), 4.39 (t, J = 7.0 Hz, 1H), 2.41 (s, 3H), 2.22-2.17 (m, 1H), 0.98 (d, J = 6.4 Hz, 6H); ESI-MS m/z 452 [M+H]+; HPLC purity: 98.44% (220nm), 97.67% (254nm).

Example 160. (2-(trifluoromethyl)pyrimidin-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -160)

To a solution of 116 (2.00 g, 11.0 mmol) in EtOH (50 mL) was added TEA (4.56 mL, 32.9 mmol) and Pd(dppf)Ch (802 mg, 1.10 mmol). The suspension was degassed in vacuo and purged with CO several times. The mixture was stirred under CO (50 psi) at 60°C for 16 h. The reaction mixture was filtered and the filtrate was concentrated. The residue was purified by silica gel column chromatography (petroleum ether/ethyl acetate = 30:1) to give 117 (600 mg, 25%) as a white solid. 1H NMR (400 MHz, CDCh) 9.16 (d, J = 4.0 Hz, 1H), 8.19 (d, J = 4.0 Hz, 1H), 4.54 (q, J = 8.0 Hz, 2H), 1.47 (t, J = 8.0Hz, 3H). To a solution of 117 (700 mg, 3.18 mmol) in THF (5 mL) and EtOH (0.5 mL) was added NaBH4 (241 mg, 6.36 mmol) at 0°C. The mixture was stirred at 0°C for 2h. The reaction was quenched with water (2 mL) slowly at 0°C and then extracted with EtOAc (5 mL x 3). The combined organic layer was washed with brine (5 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo to give 118 (500 mg, 88% yield) as a colorless oil. 1H NMR (400 MHz, CDCh) 8.90 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 4.0 Hz, 1H), 4.90 (s, 2H).

Compound 6-160 was prepared from 117, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1.1H NMR (400 MHz, DMSO-de) 9.10 (d, J = 8.0 Hz , 1H), 9.04 (s, 1H), 8.69 (d, J = 8.0 Hz, 1H), 7.93 (d, J =8.0 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.25 (d , J = 8.0 Hz, 1H), 5.40 (s, 2H), 4.97 (s, 2H), 4.44 (t, J = 8.0 Hz, 1H), 2.45 (s, 3H), 2.26 2.07 (m, 1H), 1.01 (dd, J = 8.0 Hz, 4.0 Hz, 6H); ESI-MS m/z 452 [M+H]+; HPLC purity: 99.93% (220nm), 99.54% (254nm).

Example 161. (6-(trifluoromethyl)pyrimidin-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -161)

This compound was prepared in a similar manner to Example 160 using 4-doro-6-(trifluoromethyl)pyrimidine in place of 116. 1H NMR (400 MHz, DMSO-cf) 9.43 (s, 1H), 9.04 (s, 1H), 8.72 (d, J =7.2 Hz, 1H), 8.12 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 5.47-5.37 (m, 2H ), 4.97 (s, 2H), 4.43 (t, J = 7.2 Hz, 1H), 2.44 (s, 3H), 2.23-2.19(m, 1H), 1.01 (dd, J = 6.8, 3.2 Hz, 6H) ; ESI-MS m/z 452 [M+H]+; HPLC purity: 99.09% (220nm), 97.38% (254nm).

Example 162. 1,4-Dioxepan-6-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-162)

ESI-MS m/z 392 [M+H]+; HPLC purity: 99.78% (220nm), 100% (254nm).

Example 163. 4-(2-(pyrrolidin-1-yl)ethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-163)

To a solution of 122 (J. Med. Chem. 1984, 27, 1057; 500 mg, 2.01 mmol) in THF (5.00 mL) was added LiAlH4 (153 mg, 4.02 mmol) at 0°C. The mixture was stirred at 60°C for 2h. Saturated potassium sodium tartrate solution (2 mL) was then added to the mixture at 0°C, filtered and concentrated under reduced pressure to give 123 (390 mg, 1.76 mmol, 88%) as a white solid. 1H NMR (400 MHz, CDCfe) 7.32 - 7.18 (m, 2H), 6.88 (d, J = 8.4 Hz, 2H), 4.60 (s, 2H), 4.08 (t, J = 6.2 Hz, 2H), 2.88 ( t, J = 6.0 Hz, 2H), 2.61 (s., 4H), 1.80 (dt, J = 6.8, 3.2 Hz, 4H).

Compound 6-163 was prepared from 123, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1.1H NMR (400 MHz, DMSO-cfe) 9.03 (s, 1H), 8.52 (d, J =7.9 Hz, 1H), 7.37-7.28 (m, 3H), 7.22 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 8.4 Hz, 2H), 5.17 - 5.01 (m, 2H), 4.96 (s, 2H), 4.31 (t, J = 7.3 Hz, 1H), 4.05 (t, J = 5.7 Hz, 2H), 2.76 (t, J = 5.7 Hz, 2H), 2.43 (s, 3H), 2.18-2.05 (m, 1H), 1.67 (dt, J = 6.5, 3.1 Hz, 4H), 0.92 (d, J = 6.4 Hz, 3H), 0.90 (d, J =6.4 Hz, 3H); ESI-MS m/z 495 [M+H]+; HPLC purity: 95.47% (220nm), 90.82% (254nm).

Example 164. (1-Hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alanine(6-164)

A solution of 6-002 (40 mg, 0.11 mmol) obtained in Example 2 in TFA (2 mL) and dichloromethane (2 mL) was stirred at room temperature for 1 h. Solvents were removed under reduced pressure to give 6-164 (27mg, 100%).

1H NMR (400 MHz, DMSO-cfe) 5 12.53 (b, 1H), 9.32 (s, 1H), 8.63 (s, 1H), 8.22 (s, 1H), 7.94 (d, J =8.0 Hz, 1H) , 7.47 (d, J = 7.6 Hz, 1H), 5.01 (s, 2H), 4.37 (q, J = 6.8 Hz, 2H), 1.36 (d, J = 6.8 Hz, 3H); ESI-MS: m/z 248 [MH]-; HPLC purity: 100% (220nm), 100% (254nm).

Example 165. 4-Fluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-165) To the mixture of Acid-04 (150 mg, 0.77 mmol), compound of Example B-1 (203 mg, 0.77 mmol), and DIEA (0.4 mL, 2.33 mmol) in DMF was added HATU (325 mg, 0.86 mmol). The mixture was stirred at room temperature for 3h. The crude product was purified by pre-HPLC and pre-TLC to obtain 6-165 (125 mg, 40% yield). 1H NMR (400 MHz, DMSO-d e ) 9.03 (s, 1H), 8.57 (d, J = 7.2 Hz, 1H), 7.47-7.43 (m, 2H), 7.33 (d, J = 7.6 Hz, 1H) , 7.23-7.18 (m, 3H), 5.21 (d, J =12.4 Hz, 1H), 5.11 (d, J =12.4 Hz, 1H);), 4.96 (s, 2H), 4.33 (t, J = 7.2 Hz, 1H), 2.42 (s, 3H), 2.14-2.13 (m, 1H), 0.94 (d, J = 6.8 Hz, 3H), 0.92 (d, J = 6.8 Hz, 3H); ESI-MS m/z 400 [M+H]+; HPLC purity: 100% (220nm), 100% (254nm).

Example 166. 3,4-Difluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-166)

To a solution of N-BOC-(S)-valine (2.6 g, 12.15 mmol, 1.00 eq) and (3,4-difluorophenyl)methanol (2.8 g, 19.44 mmol) in dry DCM (65 mL) was added DCC ( 4.45 g, 21.56 mmol) and DMaP (0.219 g, 1.797 mmol). The reaction mixture was stirred at 25°C for 18 hours. The mixture was filtered and washed with DCM (100 mL) and concentrated to give the crude product. The residue was purified by column chromatography (SiO ² , petroleum ether/ethyl acetate = 50/1 to 10:1) to give 3,4-difluorobenzyl(tert-butoxycarbonyl)-L-valinate (3.7 g, yield of 88%) as a sticky yellow solid. The reaction was repeated on the same scale to provide additional quantity for use in the next step.

To a stirring solution of 3,4-difluorobenzyl(tert-butoxycarbonyl)-L-valinate (5 g, 14.57 mmol) in dioxane (25 mL) was added 3N dioxane-HCL (25 mL). The reaction mixture was stirred at room temperature for 18h. After work-up, the crude compound was triturated from diethyl ether to obtain 3,4-difluorobenzyl L-valinate hydrochloride (2.65 g, 63% yield) as a white solid.

To a solution of Acid-04 (0.7 g, 3.64 mmol) in DMF (20 mL) was added 3,4-difluorobenzyl-L-valinate hydrochloride (1.06 g, 4.37 mmol), EDCI(1.04 g, 5.47 mmol), HOBt (738 mg, 5.47 mmol) and DIPEA (2.01 mL, 10.93 mmol). The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by combined flash chromatography (reverse phase) to obtain 6-166 (350 mg, 23% yield) as a white solid. 1H NMR (400 MHz, DMSO-d e ) 9.02 (s, 1H), 8.58 (d, J = 7.94 Hz, 1H), 7.54-7.39 (m, 2H), 7.35-7.17 (m, 3H), 5.15 ( s, 2H), 4.95 (s, 2H), 4.33 (t, J = 7.1 Hz, 1H), 2.41 (s, 3H), 2.20-2.08 (m, 1H), 0.94 (d, J = 6.6 Hz, 3H ), 0.92 (d, J = 6.6 Hz, 3H); ESI-MS m/z 418 [M+H]+; HPLC purity: 98.35% (220nm), 98.15% (254nm).

Example 167. 4-Chloro-3-(2-morpholinoethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6- 167)

This compound was prepared in a similar manner to Example 163. 1H NMR (400 MHz, DMSO-d e ) 89.43 (s, 1H), 9.04 (s, 1H), 8.72 (d, J =7.2 Hz, 1H), 8.12 ( s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.24 (d, J =7.6 Hz, 1H), 5.47-5.37 (m, 2H), 4.97 (s, 2H), 4.43 (t, J =7.2 Hz, 1H), 2.44 (s, 3H), 2.23-2.19(m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H); ESI-MS m/z 545 [M+H]+; HPLC purity: 96.16% (220nm), 95.23% (254nm).

Example 168. (6-(Trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -168)

This compound was prepared from (6-(trifluoromethyl)pyridin-3-yl)methanol, N-BOC-(S)-valine and Acid-04 in a similar manner to Example 1.1HRMN (400 MHz, DMSO-d e ) 9.01 (s, 1H), 8.82 (s, 1H), 8.61 (d, J = 7.5 Hz, 1H), 8.13 (d, J = 7.9 Hz, 1H), 7.95 (d, J = 7.9 Hz, 1H) , 7.45 - 7.15 (m, 2H), 5.35 (s, 2H), 4.97 (s, 2H), 4.38 (t, J = 7.3 Hz, 1H), 2.42 (s, 3H), 2.27 - 2.10 (m, 1H ), 0.96 (d, J = 6.6 Hz, 6H); ESI-MS m/z 451 [M+H]+; HPLC purity: 95.79% (220nm), 92.56% (254nm).

Example 169. 4-Fluorobenzyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate (6 -169)

To a solution of (3,4-difluorophenyl)methanol (2.43 g, 19.31 mmol) and (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoic acid (3 g, 12.87 mmol, 1.00 eq) and in dry DCM (35 mL) was added DCC (4.77 g, 23.16 mmol) and DMAP (0.471 g, 3.85 mmol). The reaction mixture was stirred at 25°C for 16 hours. The mixture was filtered and washed with DCM (100 mL) and concentrated to give the crude product. The residue was purified by combined flash chromatography (reverse phase) to give 4-fluorobenzyl (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoate (2.8 g, 64% yield) as a compound. yellow syrup.

To a stirring solution of 4-fluorobenzyl (S)-2-((tert-butoxycarbonyl)amino)-3-hydroxy-3-methylbutanoate (2.8 g, 5.27 mmol) in DCM (5 mL) at 0°C was added TFA (2ml). The reaction mixture was stirred at room temperature for 2 hours. After removing solvent and TFA by rotary evaporation, the residue was dissolved in DCM, then pH adjusted to 7, dried over Na ² SO ⁴ , concentrated to give 4-fluorobenzyl (S)-2-amino- 3-hydroxy-3-methylbutanoate (2.77 g) as a yellow syrup which was used in the next step without further purification.

To a solution of Acid-04 (67.7 mg, 0.352 mmol) in DMF (2 mL) was added 4-fluorobenzyl (S)-2-amino-3-hydroxy-3-methylbutanoate (85 mg, 0.352 mmol), EDCI (101 g, 0.529 mmol), HOBt (71.4 mg, 0.529 mmol), and DIPEA (0.25 mL, 1.41 mmol) at room temperature. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was purified by combined flash chromatography (reverse phase) to obtain 6-169 (52 mg, 35% yield) as a white solid. 1H NMR (400 MHz, DMSO-d e ) 9.06 (s, 1H), 8.23 (d, J = 8.0 Hz, 1H), 7.53 - 7.44 (m, 2H), 7.37 (d, J = 7.8 Hz, 1H) , 7.29 - 7.18 (m, 3H), 5.17 (d, J = 3.8 Hz, 2H), 4.98 (s, 2H), 4.82 (s, 1H), 4.47 (d, J = 8.0 Hz, 1H), 2.46 - 2.44 (m, 3H), 1.24 (s, 6H); ESI-MS m/z 416 [M+H]+; HPLC purity: 96.10% (220nm), 93.44% (254nm).

Example 170. 2-morpholinoethyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-170)

This compound was prepared from 2-morpholinoethane-1-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO-d e ) 8.63 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.23 (d, J = 8.0 Hz, 1H), 4.96 (s, 2H), 4.57-4.54 (m, 1H), 4.47- 4.44 (m, 1H), 4.40-4.36 (m, 1H), 3.89 (s, 2H), 3.80 (s, 2H), 3.43 (s, 4H), 3.15 (s, 2H), 2.43 (s, 3H) , 2.21-2.16 (m, 1H), 0.95 (d, J = 6.4 Hz, 6H); ESI-MS m/z 405 [M+H]+; HPLC purity: 99.93% (220nm), 100% (254nm).

Example 171. (5-(trifluoromethyl)pyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -171)

This compound was prepared from (5-(trifluoromethyl)pyridin-2-yl)methyl-L-alinate and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-da): 89.03 (s, 1H), 8.96 (s, 1H), 8.64 (d, J = 7.7 Hz, 1H), 8.27 (dd, J = 8.20, 2.0Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H) , 7.37 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.35 (s, 2H), 4.97 (s, 2H), 4.43 (t, J = 7.3 Hz, 1H) , 2.44 (s, 3H), 2.28-2.13 (m, 1H), 0.99 (d, J = 6.6 Hz, 6H); LC-MS: m/z 451.37 [M+H]+. HPLC purity: 97.38% (220nm) and chiral HPLC purity is 94.17% (210nm).

Example 172. (tetrahydro-2H-pyran-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6- 172)

A mixture of (tert-butoxycarbonyl)-L-valine (3.64 g, 16.75 mmol), 4-(bromomethyl)tetrahydro-2H-pyran (3.00 g, 16.75 mmol), and NaHcOa (2.81 g, 33.50 mmol) in DmF( 30 mL) was stirred at 70°C for 12 hours under N ² atmosphere. The reaction mixture was diluted with H ² O (100 mL) and extracted with MTBE (50 mL x 2). The combined organic layers were washed with brine (20 mL x 2), dried over Na ² SO ⁴ , filtered and concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methyl(tert-butoxycarbonyl) -L-valinate (5 g, 94.63% yield, pale yellow oil) which was used in the next step without further purification. 1H NMR (400 MHz, CDCh) 85.01 (d, J = 8.4 Hz, 1H), 4.22 (dd, J = 8.8 Hz, 4.8 Hz, 1H), 4.00-3.97 (m, 4H), 3.40 (t, J = 11.2 Hz, 2H), 2.16-2.11 (m, 1H), 1.96-1.90 (m, 1H), 1.63 (d, J = 13.2 Hz, 2H), 1.45 (s, 9H), 0.97 (d, J = 6.4 Hz, 3H), 0.90 (d, J =7.2 Hz, 3H).

To a solution of (tetrahydro-2H-pyran-4-yl)methyl(tert-butoxycarbonyl)-L-valinate (5.00 g, 15.85 mmol) in EtOAc (50 mL) was added HCl/EtOAc (6 M, 26.42 mL) . After stirring at 15°C for 2 hours, the mixture was concentrated under reduced pressure to give (tetrahydro-2H-pyran-4-yl)methyl-L-valinate hydrochloride (3.80 g, 95.23% yield) as a white solid. . 1H NMR (400 MHz, DMSO-d e ) 88.53 (br. s., 2H), 4.04 (d, J = 6.0 Hz, 2H), 3.88-3.84 (m, 3H), 3.29 (t, J =11.2 Hz , 2H), 2.21-2.17 (m, 1H), 1.91-1.86 (m, 1H), 1.59 (d, J = 13.65 Hz, 2H), 1.29-1.34 (m, 2H), 0.97 (dd, J = 16.4 , 7.2Hz, 6H).

A mixture of Acid-04 (2.00 g, 10.42 mmol), TEA (3.16 g, 31.26 mmol), and HATU (4.75 g, 12.50 mmol) in DMF (10 mL) was degassed and purged with N ² 3 times and stirred. at 15°C for 10 minutes. Next, (tetrahydro-2H-pyran-4-yl)methyl-L-valinate hydrochloride (2.75 g, 10.94 mmol) was added to the reaction mixture and stirred at 15°C for 20 minutes under N ^{2 atmosphere.} . After filtering, the mixture was purified by prep-HPLC (column: Phenomenex Synergi Max-RP 250*80 10u; liquid phase: [A-TFA/H ² O = 0.075% v/v; B-ACN] B%: 10%-40%, 20 min]) to give 6-172 (1300 g, 24.98% yield) as a white solid. 1H NMR (400 MHz, DMSO-d e ) 9.04 (brs, 1H), 8.54 (d, J = 7.6 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 7.24 (d, J = 7.6 Hz, 1H), 4.97 (s, 2H), 4.31 (t, J = 7.0 Hz, 1H), 3.96 (d, J = 6.0 Hz, 2H), 3.85 (d, J = 9.2 Hz, 2H), 3.29 ( t, J = 11.6 Hz, 2H), 2.47 (s, 3H), 2.14 (dd, J =13.2, 6.4 Hz, 1H), 1.87 (brs, 1H), 1.59 (d, J = 12.0 Hz, 2H), 1.31-1.23 (m, 2H), 0.96 (d, J = 4.4 Hz, 6H); ESI-MS m/z 390 [M+H]+; HPLC purity: 98.49% (220nm), 89.53% (254nm).

Example 173. 2-(Pyridin-2-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-173) This compound was prepared from 2-(pyridin-2-yl)ethane-1-ol, N-BOC-(S)-valine, and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO -d 6 )8.79(d, J = 5.6 Hz, 1H), 8.52-8.47(m, 2H), 8.05 (d, J = 8.0 Hz, 1H). 7.91 (t, J = 6.4 Hz, 1H), 7.30-7.28 (m, 1H), 7.24-7.22 (m, 1H), 4.97 (s, 2H), 4.61-4.51 (m, 2H), 4.24 (t, J = 7.2 Hz, 1H), 3.46 (t, J = 6.0 Hz, 2H), 2.41 (s, 3H), 2.08-1.99 (m, 1H), 0.83 (t, J = 6.4 Hz, 6H); ESI-MS m/z 397 [M+H]+; HPLC purity: 96.77% (220nm), 98.73% (254nm).

Example 174. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alaninate (6-174)

This compound was prepared from benzyl L-alaninate and Acid-01 in a similar manner to Example 1. ESI-MS m/z 340 [M+H]+; HPLC purity: 94.51% (220nm), 97.57% (254nm).

Example 175. Benzyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-D-alaninate (6-175)

This compound was prepared from benzyl D-alaninate and Acid-01 in a similar manner to Example 1. ESI-MS m/z 340 [M+H]+; HPLC purity: 91.01% (220nm), 100% (254nm).

Example 176. Methyl (S)-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-(pyridin-4-yl)propanoate (6 176)

This compound was prepared from methyl (S)-2-amino-3-(pyridin-4-yl)propanoate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 341 [M +H]+;

Example 177. Dimethyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-aspartate (6-177)

This compound was prepared from dimethyl L-aspartate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 322 [M+H]+;

Example 178. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-leuccinate (6-178)

This compound was prepared from methyl L-leucinate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 306 [M+H]+;

Example 179. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-179)

This compound was prepared from methyl L-valinate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 292 [M+H]+;

Example 180. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-alloisouccinate (6-180)

This compound was prepared from methyl L-alloisouccinate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 306 [M+H]+;

Example 181. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-phenylalaninate (6-181)

This compound was prepared from methyl L-phenylalaninate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 340 [M+H]+;

Example 182. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-tyrosinate (6-182)

This compound was prepared from methyl L-tyrosinate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 356 [M+H]+;

Example 183. Methyl (1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-tryptophanate (6-183)

This compound was prepared from methyl L-tryptophanate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 379 [M+H]+;

Example 184. Methyl (S)-3-cyclopropyl-2-(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)propanoate (6 184)

This compound was prepared from methyl (S)-2-amino-3-cyclopropylpropanoate and Acid-01 in a similar manner to the last step of Example 1. ESI-MS m/z 304 [M+H]+;

Example 185. 3,4-Difluorobenzyl(1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-185)

This compound was prepared from 3,4-difluorobenzyl L-valinate and Acid-01 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.31 (s, 1H), 8.69 ( d, J = 7.7 Hz, 1H), 8.24 (s, 1H), 7.95 (dd, J = 7.9, 1.7Hz, 1H), 7.53-7.37 (m, 3H), 7.30-7.20 (m, 1H), 5.15 (s, 2H), 5.05 (s, 2H), 4.34 (t, J = 7.5 Hz, 1H), 2.22 (qd, J =13.8 Hz, 1H), 0.98 (d, J = 6.6 Hz, 3H), 0.96(d, J = 6.6 Hz, 3H); LC-MS: m/z 404.40 [M+H]+ HPLC purity: 98.78% (220nm), 97.43% (254nm), chiral Hp LC purity is 96.73% (232nm).

Example 186. Pyrazin-2-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-186)

This compound was prepared from pyrazin-2-ylmethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-da): 59.03 (s, 1H), 8.77 (d, J = 1.5 Hz, 1H), 8.69-8.52 (m, 3H), 7.36 (d, J = 7.3 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.41 - 5.24 (m , 2H), 4.97 (s, 2H), 4.47 - 4.30 (m, 1H), 2.43 (s, 3H), 2.19 (qd, J =13.3, 6.8, Hz, 1H), 0.97 (dd, J = 6.8, 2.4Hz, 6H); LC-MS: m/z 384.05 [M+H]+. HPLC purity: 95.93% (220nm), 95.25% (254nm) and chiral HPLC purity is 97.38% (220nm).

Example 187. Pyridin-3-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-187)

This compound was prepared from pyridin-3-ylmethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6): 59.03 (s, 1H), 8.70 - 8.46 (m, 3H), 7.82 (br d, J = 7.8 Hz, 1H), 7.42 (dd, J = 7.8, 4.9Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 5.31 - 5.16 (m, 2H), 4.97 (s, 2H), 4.35 (brt, J = 7.3 Hz, 1H), 2.42 (s, 3H), 2.21 - 2.09 (m, 1H ), 0.93 (dd, J = 2.0, 6.8 Hz, 6H); LC-MS: m/z 383.35 [M+H]+. HPLC purity: 98.95% (220nm), 98.46% (254nm) and chiral HPLC purity is 95.05% (215nm).

Example 188. tert-Butyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-188)

This compound was prepared from (s)-valine t-butyl ester and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-da): 59.03 (s, 1H) , 8.39 (d, J = 7.8 Hz, 1H), 7.36 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.18 (dd, J = 7.8, 6.8 Hz, 1H), 2.49 - 2.42 (m, 3H), 2.11 (qd, J = 13.7, 6.8 Hz, 1H), 1.44 (s, 9H), 0.95 (d, J = 5.9 Hz, 6H); LC-MS: m/z 348.19 [M+H]+. HPLC purity: 98.79% (220nm) and chiral HPLC purity is 96.91% (211nm).

Example 189. (6-cyanopyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-189)

This compound was prepared from (6-cyanopyridin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-da): 59.03 (s , 1H), 8.69 - 8.54 (m, 1H), 8.17 - 8.08 (m, 1H), 8.01 (d, J = 7.3 Hz, 1H), 7.83 (d, J = 7.8 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.39 - 5.20 (m, 2H), 4.97 (s, 2H), 4.41 (t, J =7.1 Hz, 1H), 2.44 ( s, 3H), 2.28-2.14 (m, 1H), 1.00 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H); LC-MS: m/z 408.46 [M+H]+. HPLC purity: 98.89% (220nm), 97.41% (254nm) and chiral HPLC purity is 99.44% (210nm).

Example 190. Pyridin-4-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-190)

This compound was prepared from pyridin-4-ylmethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-da): 89.04 (brs, 1H), 8.65 ( brd, J =7.7 Hz, 1H), 8.57 (d, J = 5.9 Hz, 2H), 7.46 7.33 (m, 3H), 7.24 (d, J = 7.7 Hz, 1H), 5.24 (s, 2H), 4.97 (s, 2H), 4.40 (t, J = 7.2 Hz, 1H), 2.44 (s, 3H), 2.20 (br dd, J = 13.4, 6.8 Hz, 1H), 0.99 (d, J = 6.6 Hz, 3H ), 0.96 (d, J = 6.6 Hz, 3H); LC-MS: m/z 383.32 [M+H]+. HPLC purity: 97.2% (220nm) and chiral HPLC purity is 95.08% (212nm).

Example 191. Pyridin-2-ylmethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-191)

This compound was prepared from pyridin-2-ylmethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (400 MHz, DMSO-d6): 89.03 (s, 1H), 8.61 (d, J = 7.8 Hz, 1H), 8.56 (brd, J = 3.9 Hz, 1H), 7.83 (dt, J = 7.6, 1.5 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.41 -7.31 (m, 2H), 7.24 (d, J =7.8 Hz, 1H), 5.33-5.13 (m, 2H), 4.97 (s, 2H), 4.41 (t, J = 7.3 Hz, 1H), 2.44 ( s, 3H), 2.20 (qd, J = 13.5, 6.8 Hz, 1H), 0.97 (dd, J = 6.8, 1.5 Hz, 6H); LC-MS: m/z 383.45 [M+H]+. HPLC purity: 99.25% (220nm), 98.10% (254nm) and chiral HPLC purity is 98.92% (210nm).

Example 192. Benzyl (7-ethoxy-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-192)

This compound was prepared from L-valine benzyl ester and Acid-13 in a similar manner to the last step of Example 1.1H NMR (300 MHz, DMSO-d6): 89.36 (s, 1H), 8.71 (d, J = 8.1 Hz, 1H), 7.97 (d, J = 7.7 Hz, 1H), 7.53 -7.27 (m, 5H), 7.16 (d, J = 7.7 Hz, 1H), 5.30 - 5.10 (m, 2H), 5.01 (s, 2H), 4.62 - 4.30 (m, 3H), 2.31 - 2.03 (m, 1H), 1.32 (t, J = 7.0 Hz, 3H), 0.93 (d, J = 7.0 Hz, 6H); LC-MS: m/z 412.01 [M+H]+. HPLC purity: 99.77% (220nm) and 99.36% (254nm) and chiral HPLC purity is 99.73% (210nm).

Example 193. (6-morpholinopyrazin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 193)

This compound was prepared from (6-morpholinopyrazin-2-yl)methyl-L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.07 ( s, 1H), 8.63 (br d, J = 8.1 Hz, 1H), 8.28 (s, 1H), 7.96 (s, 1H), 7.35 (d, J =7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 5.19-5.03 (m, 2H), 4.97 (s, 2H), 4.39 (brt, J = 7.2 Hz, 1H), 3.81 - 3.63 (m, 4H), 3.59 - 3.47 (m, 4H ), 2.44 (s, 3H), 2.18 (br dd, J = 13.4, 6.4 Hz, 1H), 0.97 (br d, J = 6.6 Hz, 6H); LC-MS: m/z 468.99 [M+H]+. HPLC purity: 97.87% (220nm), 97.59% (254nm) and chiral HPLC purity is 98.56% (252nm).

Example 194. Benzyl (1-hydroxy-7-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-194)

This compound was prepared from L-valine benzyl ester and Acid-12 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-da): 89.39 (s, 1H), 8.62 (d , J = 8.1 Hz, 1H), 7.87 (d, J = 7.7 Hz, 1H), 7.57 -7.30 (m, 5H), 7.16 (d, J = 7.7 Hz, 1H), 5.29 - 5.09 (m, 2H) , 5.02 (s, 2H), 4.49 (dd, J = 8.1, 5.5 Hz, 1H), 4.07 (s, 3H), 2.20 (dt, J = 13.0, 6.6 Hz, 1H), 0.93 (dd, J = 4.0 , 6.6Hz, 6H); LC-MS: m/z 398.40 [M+H]+. HPLC purity: 99.03% (220nm), chiral HPLC purity is 99.71% (215nm).

Example 195. 4-Fluorobenzyl (1-hydroxy-7-methoxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-195)

This compound was prepared from 4-fluorobenzyl L-valinate and Acid-12 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.39 (s, 1H), 8.62 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.1 Hz, 1H), 7.46 (dd, J = 8.6, 5.7 Hz, 2H), 7.30 - 7.02 (m, 3H), 5.27 - 5.09 (m, 2H ), 5.02 (s, 2H), 4.48 (dd, J = 7.7, 5.5 Hz, 1H), 4.07 (s, 3H), 2.30-2.07 (m, 1H), 0.93 (d, J = 6.6 Hz, 3H) , 0.91 (d, J = 6.6 Hz, 3H); 0.92 (dd, J = 4.0, 6.6 Hz, 6H); LC-MS: m/z 416.38 [M+H]+. HPLC purity: 99.3% (220nm), chiral HPLC purity is 98.89% (217nm).

Example 196. 4-Fluorobenzyl(7-ethoxy-1-hydroxy-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-196)

This compound was prepared from 4-fluorobenzyl L-valinate and Acid-13 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6): 89.35 (s, 1H), 8.70 (d, J = 8.3 Hz, 1H), 7.96 (d, J = 7.8 Hz, 1H), 7.54-7.41 (m, 2H), 7.30-7.07 (m, 3H), 5.27-5.12 (m, 2H), 5.01 (s , 2H), 4.61-4.33 (m, 3H), 2.23-2.08 (m, 1H), 1.32 (t, J =7.1 Hz, 3H), 0.92 (d, J = 5.9 Hz, 6H); LC-MS: m/z 430.38 [M+H]+. HPLC purity: 99.23% (220nm) and chiral HPLC purity is 97.74% (218nm).

Example 197. (6-morpholinopyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 197)

This compound was prepared from (6-morpholinopyridin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.04 (s , 1H), 8.59 (br d, J = 7.7 Hz, 1H), 7.61 - 7.51 (m, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.83-6.69 (m, 2H), 5.11 - 5.02 (m, 2H), 4.97 (s, 2H), 4.40 (t, J = 7.3 Hz, 1H), 3.72 - 3.62 (m, 4H), 3.49- 3.38 (m, 4H), 2.45 (s, 3H), 2.24-2.13 (m, 1H), 0.97 (d, J = 6.6 Hz, 6H); LC-MS: m/z 468.43 [M+H]+. HPLC purity: 97.75% (220 nm) and 99.50% (254 nm); chiral HPLC purity is 98.07% (248 nm).

Example 198. (R)-1-phenylethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-198)

This compound was prepared from (R)-1-phenylethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.03 (s, 1H) , 8.58 (d, J = 8.1 Hz, 1H), 7.48 - 7.28 (m, 6H), 7.28 - 7.19 (m, 1H), 5.89 (q, J = 6.6 Hz, 1H), 4.97 (s, 2H), 4.33 (t, J = 7.5 Hz, 1H), 2.46 (s, 3H), 2.16 (qd, J = 13.6, 6.7 Hz, 1H), 1.49 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.8 Hz, 1H), 0.94 (d, J = 6.8 Hz, 3H); LC-MS: m/z 396.45 [M+H]+. HPLC purity: 98.07% (220 nm) and 96.63% (254 nm); chiral HPLC purity is 97.84% (214 nm).

Example 199. (S)-1-phenylethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-199)

This compound was prepared from (S)-1-phenylethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.03 (s, 1H) , 8.51 (d, J = 8.1 Hz, 1H), 7.52 - 7.30 (m, 6H), 7.28 - 7.17 (m, 1H), 5.87 (q, J = 6.6 Hz, 1H), 4.97 (s, 2H), 4.36 (dd, J =7.9, 6.4 Hz, 1H), 2.44 (s, 3H), 2.17 (qd, J = 6.7, 13.4 Hz, 1H), 1.51 (d, J = 6.6 Hz, 3H), 0.89 (dd , J = 13.8, 6.8Hz, 6H); LC-MS: m/z 396 [M+H]+. HPLC purity: 99.08% (220nm) and chiral HPLC purity is 98.31% (210nm).

Example 200. (5-cyanopyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-200)

This compound was prepared from (5-cyanopyridin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.08-8.94 (m, 2H), 8.66 (d, J = 7.3 Hz, 1H), 8.38 (dd, J = 2.2, 8.4 Hz, 1H), 7.70 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 5.50 - 5.21 (m, 2H), 4.97 (s, 2H), 4.42 (t, J = 7.2 Hz, 1H), 2.47 (d, J =13.2 Hz, 3H), 2.21 (qd, J = 13.7, 7.0 Hz, 1H), 0.99 (dd, J = 6.8, 1.3 Hz, 6H); LC-MS: m/z 408.36 [M+H]+. HPLC purity: 97.57% (220nm) and chiral HPLC purity is 98.17% (215nm).

Example 201. (6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-201)

This compound was prepared from (6-(4-methylpiperazin-1-yl)pyridin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz , DMSO-da): 89.05 (br s, 1H), 8.61 (br d, J = 7.7 Hz, 1H), 7.75-7.57 (m, 1H), 7.36 (d, J = 7.7 Hz, 1H), 7.29- 7.19 (m, 1H), 6.98-6.74 (m, 2H), 5.09 (s, 2H), 4.98 (s, 2H), 4.56 4.29 (m, 3H), 3.50 (br d, J = 8.8 Hz, 2H) , 3.08 (br d, J = 10.6 Hz, 4H), 2.90 - 2.69 (m, 3H), 2.45 (s, 3H), 2.27 - 2.10 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H) ; LC-MS: m/z 481.46 [M+H]+ HPLC purity: 98.11% (220nm), 98.54% (254nm) and chiral HPLC purity is 98.33% (245nm).

Example 202. (5-Fluoropyrimidin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 202)

This compound was prepared from (5-fluoropyrimidin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.04 (s , 1H), 8.92 (d, J = 0.7 Hz, 2H), 8.58 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H ), 5.33 (m, 2H), 4.97 (s, 2H), 4.47 (dd, J = 6.4, 7.9 Hz, 1H), 2.45 (s, 3H), 2.25 (qd, J = 6.7, 13.3 Hz, 1H) , 1.00 (dd, J = 6.6, 2.2 Hz, 6H); LC-MS: m/z 402.39 [M+H]+. HPLC purity: 98.58% (220nm) and chiral HPLC purity is 98.47% (210nm).

Example 203. (4-(trifluoromethyl)pyrimidin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -203)

This compound was prepared from (4-(trifluoromethyl)pyrimidin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.20 (d, J = 5.1 Hz, 1H), 9.03 (s, 1H), 8.58 (d, J = 8.1 Hz, 1H), 7.99 (d, J = 5.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.23 (d, J = 7.7 Hz, 1H), 5.57 - 5.28 (m, 2H), 4.97 (s, 2H), 4.62 - 4.38 (m, 1H), 2.46 (s, 3H), 2.27 (qd, J = 6.7, 13.3 Hz, 1H), 1.03 (dd, J = 2.8, 6.8 Hz, 6H); LC-MS: m/z 452.36 [M+H]+. HPLC purity: 96.72% (220nm) and chiral HPLC purity is 95.23% (215nm).

Example 204. (6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-204)

This compound was prepared from (6-(4-methylpiperazin-1-yl)pyrazin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz , DMSO-d6): 89.06 (s, 1H), 8.62 (brd, J = 7.7 Hz, 1H), 8.27 (s, 1H), 7.91 (s, 1H), 7.35 (d, J = 7.7 Hz, 1H) , 7.23 (d, J = 7.7 Hz, 1H), 5.22 - 5.03 (m, 2H), 4.97 (s, 2H), 4.46 - 4.31 (m, 1H), 3.56 (br s, 4H), 2.50 - 2.33 ( m, 7H), 2.30 - 1.97 (m, 4H), 0.96 (d, J = 6.6 Hz, 6H). LC-MS: m/z 482 [M+H]+. HPLC purity: 98.14% (220nm), 99.12% (254nm) and chiral HPLC purity is 99.11% (210nm).

Example 205. (6-(piperazin-1-yl)pyrazin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L -valinate (6-205)

To a stirring solution of 124 (1.5 g, 8.72 mmol) in NMP (10 vol) was added DIPEA (7.6 mL, 43.60 mmol) and N-Boc-piperazine (3.24 g, 17.44 mmol) at room temperature. The reaction mixture was stirred at 100°C for 16h. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with water and extracted with ethyl acetate (3 x 100 mL). The combined organic layer was concentrated under reduced pressure to obtain crude material. The crude compound was purified by silica gel column chromatography (100-200 mesh, 15-20% EtOAc:petroleum ether) to yield 125 (1 g, 35%) as a colorless liquid. To a stirring solution of 125 (1 g, 3.10 mmol) in dry THF (10 mL) was added a solution of LiAlH ⁴ (2 M in THF, 0.776 mL, 1.55 mmol) dropwise at -20°C and stirred at the same temperature for 2 h. The progress of the reaction was monitored by TLC. TLC showed the formation of a polar spot with complete consumption of starting material. The reaction was quenched with saturated sodium sulfate and the reaction mixture was filtered through a pad of celite. The filtrate was evaporated under reduced pressure to obtain crude residue. The crude compound was purified by silica gel column chromatography (100-200 mesh, 25-28% EtOAc:petroleum ether) to yield 126 (500 mg, 54%) as a pale yellow solid. To a stirring solution of 126 (500 mg, 1.70 mmol) in DCM (10 vol) was added TEA (0.715 mL, 5.10 mmol) and methanesulfonyl chloride (0.197 mL, 2.55 mmol) dropwise at 0°C. The reaction mass was stirred at room temperature for 2h. TLC showed the formation of a non-polar spot with complete consumption of starting material. The reaction mixture was concentrated under reduced pressure to obtain 400 mg of crude 127 as a yellow syrup. The crude compound was used as such in the next step without further purification. To a stirring solution of 6-103 (375.4 mg, 1.29 mmol) in DMF (20 mL) was added K ² CO ³ (355.6 mg, 2.57 mmol) at room temperature and stirred at room temperature for 10 min. Then 127 (400 mg, crude, 1075 mmol) in DMF was added dropwise at room temperature. The reaction mass was heated at 90°C for 16h. The reaction mixture was quenched with ice water and extracted into EtOAc (2 x 100 mL). The combined organic layers were washed with water, brine and dried over Na ² ¿O ⁴ . The solvent was removed under reduced pressure to obtain crude material. The crude compound was purified by C-18 column with 0.01% HCOOH in water and acetonitrile] to give 128 (95 mg, 10%) as a white solid. To a stirring solution of 128 (90 mg, 0.158 mmol) in 1,4-dioxane (10 vol) was added 4M HCl-dioxane (10 mL) at 0°C. The reaction mixture was stirred at room temperature for 2h. The solvent was removed under reduced pressure to obtain the residue, which was triturated with ether to obtain 85 mg of 6-205 as HCl salt. 1H NMR (400 MHz, DMSO-d ⁶ ): ⁸ 9.14 (br s, 3h), 8.61 (br d, J = 7.8 Hz, 1H), 8.36 (s, 1H), 8.02 (s, 1H), 7.40 - 7.31 (m, 1H), 7.24 (d, J = 7.8 Hz, 1H), 5.24 - 5.06 (m, 2H), 4.97 (s, 2H), 4.47 - 4.35 (m, 1H), 3.90 - 3.76 (m, 4H), 3.17 (br s, 4H), 2.49-2.37 (m, 3H), 2.22-2.11 (m, 1H), 0.97 (br d, J = ^6.8 Hz, ⁶ H). LC-MS: m/z 468.34 [M+H]+. HPLC purity: 95.10% (220nm), 96.29% (254nm) and chiral HPLC purity is 95.97% (247nm).

Example 206 2-(2,6-dimethylmorpholino)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate ( ⁶ 206)

This compound was prepared from 2-(2,6-dimethylmorpholino)ethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400MHz, DMSO-d ⁶ ): ⁸ 9.03 (s, 1H), 8.49 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.25-7.16 (m, 1H), 4.97 (s, 2H), 4.33-4.22 ( m, 2H), 4.15 (td, J =11.5, 5.5 Hz, 1H), 3.51 (br dd, J =3.7, 6.1 Hz, 2H), 2.76 (br d, J = 10.3 Hz, 2H), 2.51 (br s, 2H), 2.47 (s, 3H), 2.14 (qd, J = 13.7, ^6.8 Hz, 1H), 1.67 (br d, J = 8.3 Hz, 2H), 1.07 - 0.90 (m, 12H). LC-MS: m/z 433.38 [M+H]+. HPLC purity: 95.98% (220nm) and chiral HPLC purity is 95.04% (211nm).

Example 207 2-morpholinopropyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-207)

This compound was prepared from 2-(3-methylmorpholino)ethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300MHz, DMSO-da): 89.04 (br s, 1H), 8.50 (br d, J = 7.7 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.97 (s, 2H), 4.42 - 4.13 (m, 2H), 4.06 - 3.85 (m, 1H), 3.67 - 3.44 (m, 4H), 2.89 -2.69 (m, 1H), 2.48 - 2.36 (m, 7H), 2.23 - 2.06 (m, 1H) , 0.96-0.94 (m, superimposed, 9H); LC-MS: m/z 419.32 [M+H]+ purity by Hp LC is 99.11% (220nm).

Example 208. 3-morpholinopropyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-208)

This compound was prepared from 3-morpholinopropyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300MHz, DMSO-d6): 89.04 (br s, 1H), 8.51 (br d , J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.28-7.16 (m, 1H), 4.97 (s, 2H), 4.35-4.25 (m, 1H), 4.19-4.04 ( m, 2H), 3.72-3.49 (m, 4H), 2.48 (d, J = 5.5 Hz, 3H), 2.42-2.27 (m, 6H), 2.21 -2.05(m, 1H), 1.76 (q, J = 6.7 Hz, 2H), 0.96 (d, J = 6.6 Hz, 6H). LC-MS: m/z: 419.29 [M+H]+ HPLC purity: 97.20% (220 nm) and chiral HPLC purity is 95.25% (218 nm)

Example 209. 3-Hydroxy-3-methylbutyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-209)

This compound was prepared from 3-hydroxy-3-methylbutyl L-valinate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (300MHz, DMSO-d6): 89.04 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 4.97 (s, 2H), 4.38 (s, 1H), 4.32-4.25 (m, 1H), 4.22-4.14 (m, 2H), 2.50-2.42 (m, 3H), 2.23 2.02 (m, 1H), 1.72 (t, J = 7.5 Hz, 2H), 1.12 (s , 6H), 0.95 (d, J = 7.0 Hz, 6H). LC-MS: m/z 378.29[M+H]+. HPLC purity: 97% (220nm) and chiral HPLC purity is 97.9% (219nm).

Example 210. (tetrahydrofuran-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 210)

This compound was prepared from cyclopentylmethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (300 MHz, DMSO-d6): 89.03 (s, 1H), 8.61 -8.45 (m, 1H ), 7.38 (d, J =7.7 Hz, 1H), 7.24 (d, J = 8.1 Hz, 1H), 4.97 (s, 2H), 4.32 (t, J = 7.2 Hz, 1H), 4.17-3.95 (m , 3H), 3.83 - 3.54 (m, 2H), 2.47 (s, 3H), 2.14 (qd, J =13.5, 6.9 Hz, 1H), 2.00- 1.73 (m, 3H), 1.60 (brdd, J = 9.0 , 6.1 Hz, 1H), 0.96 (d, J = 6.6 Hz, 6H); LC-MS: m/z 376.24 [M+H]+ HPLC purity: 96.93% (220 nm).

Example 211. 2-Hydroxy-2-methylpropyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-211)

This compound was prepared from 2-hydroxy-2-methylpropyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-da): 89.04 (s, 1H ), 8.51 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.98 (s, 2H), 4.58 (br s, 1H), 4.40 (dd, J = 6.4, 7.9 Hz, 1H), 3.86 (s, 2H), 2.47 (s, 3H), 2.18 (qd, J = 6.7, 13.5 Hz, 1H), 1.13 (s, 6H ), 0.99 (d, J = 7.0 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H); . LC-MS: m/z 364.28 [M+H]+. HPLC purity: 99.4% (220nm) and chiral HPLC purity is 97.03% (212nm).

Example 212 2-(2-oxopyrrolidin-1-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 212 )

This compound was prepared from 2-(2-oxopyrrolidin-1-yl)ethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300MHz, DMSO-d6) 89.04 ( br s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 4.97 (s, 2H), 4.36 - 4.27 (m, 1H), 4.20 (t, J = 5.5 Hz, 2H), 3.50 - 3.33 (m, 4H), 2.48 (d, J = 5.5 Hz, 3H), 2.29 - 2.06 (m, 3H), 1.89 (quin, J = 7.4 Hz, 2H), 0.94 (d, J = 6.6 Hz, 6H); LC-MS: m/z 403.28 [M+H]+. HPLC purity: 96.7% (220nm) and chiral HPLC purity is 98.12% (215nm).

Example 213. (6-(piperazin-1-yl)pyridin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L -valinate (6-213)

This compound was prepared from methyl 6-chloropicolinate in a similar manner to Example 205. 1H NMR (400 MHz, DMSO-d6): 89.10 (br s, 2H), 8.60 (br d, J =7.8 Hz, 1H ), 7.72- 7.60 (m, 1H), 7.36 (d, J =7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 6.87 (d, J = 8.3 Hz, 1H), 6.81 (d , J = 7.3 Hz, 1H), 5.09 (s, 2H), 4.97 (s, 2H), 4.57 - 4.29 (m, 1H), 3.79 -3.66 (m, 4H), 3.15 (br s, 4H), 2.49 - 2.39 (m, 3H), 2.20 (qd, J = 13.6, Hz, 1H), 0.98 (d, J = 6.8 Hz, 6H). LC-MS: m/z 467.35 [M+Na]+. HPLC purity: 97.48% (220nm) and chiral HPLC purity is 96.58% (246nm).

Example 214. 2-(1,4-oxazepan-4-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate ( 6 214)

To a stirring solution of 6-003 (1.00 g, 3.43 mmol) in DMF (10 mL) was added K ² CO ³ (948 mg, 6.87 mmol) at room temperature. The reaction mixture was stirred at room temperature for 10 min. 1,2-Dibromoethane (2.9 mL, 34.36 mmol) was then added at room temperature. The reaction mixture was irradiated in microwave at 80°C for 30 min. The progress of the reaction was monitored by TLC. The reaction mixture was quenched with ice water and extracted into EtOAc (2 x 100 mL). The combined organic layers were washed with water, brine, and dried over Na ² SO ⁴ . The solvent was removed under reduced pressure to obtain 129 (800 mg, 59%) as an off-white solid. To a stirring solution of 1,4-oxazepane hydrochloride (200 mg, 1.98 mmol) in DMF (10 vol) was added 129 (786 mg, 1.98 mmol) and potassium carbonate (819 mg, 5.94 mmol) at room temperature . The reaction mixture was stirred at 80°C for 1h. The progress of the reaction was monitored by TLC. TLC showed the formation of a non-polar spot with complete consumption of both starting materials. Solvent was removed under reduced pressure to obtain crude material. The crude compound was purified by [C-18 column with 0.1% HCOOH in water and acetonitrile] to give 6-214 (181 mg, 22%) as an off-white gummy solid. 1H NMR (400 MHz, DMSO-d6): 89.03 (s, 1H), 8.52 (br d, J = 7.3 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.38 - 4.07 (m, 3H), 3.71 - 3.47 (m, 4H), 2.97 - 2.63 (m, 6H), 2.47 (s, 3H), 2.15 (qd, J = 13.3, 6.8 Hz, 1H), 1.86 -1.76 (m, 2H), 0.97 (d, J = 6.8 Hz, 6H); LC-MS: m/z 419.35 [M+H]+. HPLC purity: 97.02% (220nm) and chiral HPLC purity is 97.7% (215nm).

Example 215. ((R)-tetrahydrofuran-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 215 )

This compound was prepared from ((R)-tetrahydrofuran-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400MHz, DMSO-d6): 89.03 ( s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.36- 4.27 (m, 1H), 4.20-4.09 (m, 1H), 4.06-3.95 (m, 2H), 3.80 - 3.72 (m, 1H), 3.70 - 3.60 (m, 1H), 2.47 (s, 3H), 2.21 -2.08 (m, 1H), 2.01 - 1.74 (m, 3H), 1.61 (ddd, J = 11.9, 8.4, 6.6 Hz, 1H), 0.98 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H) LC-MS: m/z 376.28 [M+H]+. HPLC purity: 97.39% (220nm) and chiral HPLC purity is 96.76% (225nm).

Example 216 2-(2-oxooxazolidin-3-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 216 )

This compound was prepared from 2-(2-oxooxazolidin-3-yl)ethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6): 89.03 (s, 1H), 8.52 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.34-4.29 (m, 1H), 4.28-4.17 (m, 4H), 3.60 (t, J =8.1 Hz, 2H), 3.50 3.39 (m, 2H), 2.47 (s, 3H), 2.14 (dd, J =13.5, 6.6 Hz, 1H), 0.95 (d, J = 6.8 Hz, 6H); LC-MS: m/z 405.26 [M+H]+. HPLC purity: 99.25% (220nm) and chiral HPLC purity is 98.99% (211nm).

Example 217. 2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl )-L-valinate (6-217)

This compound was prepared from 2-oxa-7-azaspiro[3.5]nonane in a similar manner to the last step of Example 214. 1H NMR (300MHz, DMSO-da): 89.04 (s, 1H), 8.53 (brd, J = 7.3 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.25 (br d, J = 7.7 Hz, 1H), 4.98 (s, 2H), 4.40 - 4.08 (m, 7H), 2.95 - 2.51 (m, 6H), 2.47 (br s, 3H), 2.14 (br dd, J = 13.8, 6.8 Hz, 1H), 1.79 (br s, 4H), 0.96 (d, J = 6.6 Hz, 6H). LC-MS: m/z 445.4 [(M+H)+]. HPLC purity: 93.46% (220 nm) and chiral HPLC purity is 96.16% (211 nm).

Example 218. 2-(2-oxa-6-azaspiro[3.3]heptan-6-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl )-L-valinate (6-218)

This compound was prepared from 2-oxa-6-azaspiro[3.3]heptane in a similar manner to the last step of Example 214. 1H NMR (300 MHz, DMSO-d6): 89.04 (br s, 1H), 8.52 (br d, J = 8.1 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.98 (s, 2H), 4.58 (s, 4H), 4.32 (t, J = 7.2 Hz, 1H), 4.06 (br t, J = 5.3 Hz, 2H), 3.50 (br s, 4H), 2.73 (brs, 2H), 2.48 (brs, 3H), 2.24-2.04 (m, 1H), 0.96 (d, J =7.0 Hz, 6H). LC-MS: 417.31 [M+H]+. HPLC purity: 97.53% and chiral HPLC purity is 99.04% (212nm).

Example 219. 2-(3-Methylmorpholino)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-219)

This compound was prepared from 2-(3-methylmorpholino)ethyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400MHz, DMSO-d6): 89.04 (br s, 1H), 8.69 - 8.41 (m, 1H), 7.38 (d, J =7.3 Hz, 1H), 7.25 (brd, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.53 - 3.96 (m, 4H ), 3.77 - 3.34 (m, 4H), 3.12-2.86 (m, 2H), 2.75 (brs, 1H), 2.48 (s, 3H), 2.41 - 2.24 (m, 2H), 2.15 (br s, 1H) , 1.32 - 1.11 (m, 1H), 1.03 - 0.84 (m, 7H); LC-MS: m/z 419.35[M+H]+. HPLC purity: 99.61% (220nm).

Example 220. (1-Hydroxycyclopentyl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 220)

This compound was prepared from (1-hydroxycyclopentyl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400MHz, DMSO-d6): 89.03 (s, 1H), 8.49 (d, J = 8.2 Hz, 1H), 7.38 (d, J =7.6 Hz, 1H), 7.25 (d, J = 7.9 Hz, 1H), 4.97 (s, 2H), 4.49 (s, 1H), 4.39 (dd, J = 7.9, 6.4 Hz, 1H), 4.09 - 3.94 (m, 2H), 2.47 (s, 3H), 2.18 (qd, J =13.4, 6.7 Hz, 1H), 1.71 (brd, J = 4.0 Hz, 2H), 1.55 (brs, 6H), 0.98 (d, J =7.0 Hz, 3H); 0.94 (d, J = 7.0 Hz, 3H); LC-MS: m/z 387.82[M+H]+. HPLC purity: 97.94% (220nm) and chiral HPLC purity is 97.86% (213nm).

Example 221 4-Fluorobenzyl 3-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)oxetane-3-carboxylate (6-221)

This compound was prepared from 4-fluorobenzyl 3-aminooxetane-3-carboxylate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (300 MHz, DMSO-da): 89.48 (s, 1H), 9.07 (brs, 1H), 7.57-7.35 (m, 3H), 7.32 - 7.02 (m, 3H), 5.22 (s, 2H), 5.04 - 4.84 (m, 4H), 4.67 (d, J = 6.6 Hz, 2H), 2.42 (s, 3H); LCMS: m/z 400.27[M+H]+. HPLC purity: 95.08% (220nm).

Example 222 2-morpholinoethyl 3-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)oxetane-3-carboxylate (6-222)

This compound was prepared from 2-morpholinoethyl 3-aminooxetane-3-carboxylate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.47 (s, 1H ), 9.08 (s, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.29 (br d, J = 7.7 Hz, 1H), 5.09 - 4.87 (m, 4H), 4.67 (br d, J = 6.6 Hz, 2H), 4.31 (br s, 2H), 3.54 (br s, 4H), 2.52 (br s, 6H), 2.47-2.17 (m, 3H); LC-MS: m/z 404.8 [M+H]+ HPLC purity: 97.2% (220nm).

Example 223 Pyridin-2-ylmethyl 3-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)oxetane-3-carboxylate (6-223)

This compound was prepared from pyridin-2-ylmethyl 3-aminooxetane-3-carboxylate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.54 (s, 1H), 9.07 (s, 1H), 8.56 (d, J = 4.0 Hz, 1H), 7.92 - 7.77 (m, 1H), 7.49 - 7.42 (m, 2H), 7.35 (dd, J = 7.2, 5.3 Hz , 1H), 7.26 (d, J = 7.7 Hz, 1H), 5.31 (s, 2H), 5.04 -4.93 (m, 4H), 4.71 (d, J = 6.6 Hz, 2H), 2.44 (s, 3H) : LC-MS: m/z 383.24 [M+H]+. HPLC purity: 99.27% (220nm).

Example 224 Cyclopentylmethyl 3-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)oxetane-3-carboxylate (6-224)

This compound was prepared from cyclopentylmethyl 3-aminooxetane-3-carboxylate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (400 MHz, DMSO-d6): 89.44 (s, 1H), 9.08 (s, 1H), 7.48 (d, J = 7.7 Hz, 1H), 7.29 (d, J = 7.7 Hz, 1H), 4.99 (s, 2H), 4.91 (d, J = 6.6 Hz, 2H), 4.66 (d, J = 6.6 Hz, 2H), 4.06 (d, J =7.0 Hz, 2H), 2.47 (br s, 3H), 2.26 - 2.11 (m, 1H), 1.77 -1.61 (m, 2H), 1.60 - 1.40 (m, 4H), 1.25 (br dd, J = 6.8, 11.9 Hz, 2H); LC-MS: m/z 374.3 [M+H]+. HPLC purity: 97.32% (220 nm).

Example 225. (2-Aminopyrimidin-5-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate ( ⁶ 225)

To a stirred suspension of 130 (500 mg, 4 mmol) in DCM (10 mL) was added SOCI ² (1 mL) dropwise at 0°C. After addition was complete, the reaction mixture was left at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure to obtain 290 mg of crude 131 as HCl salt. The crude compound as such was carried to the next step without further purification. To a stirring solution of 6-003 (582 mg, 2 mmol) in DMF (10 mL) was added 131 (290 mg, crude, 2 mmol) and K ² CO ³ (828 mg, ⁶ mmol) at room temperature. The reaction mixture was irradiated in microwave at 80°C for 1 h. The progress of the reaction was monitored by TLC. Solvent was removed under reduced pressure to obtain crude material. The crude compound was purified by Grace Purification system [C-18 column with 0.01% HCOOH in water and acetonitrile] to give 500 mg of crude 6-225. The crude compound was purified by preparative HPLC purification to obtain 6-225 (60 mg, 4% over two steps) as a white solid. 1H NMR (400 MHz, DMSo-d ⁶ ): ⁸ 9.03 (br s, 1h), 8.53 (br d, J = 7.8 Hz, 1H), 8.31 (s, 2H), 7.35-7.30 (d, J = 7.3 Hz, 1H), 7.23 (d, J = 7.3 Hz, 1H), 7.09-6.84 (m, 2H), 5.13-4.85 (m, 4H), 4.37-4.22 (m, 1H), 2.43 (s, 3H) , 2.11 (qd, J = 13.3, 6.3 Hz, 1H), 0.92 (d, J = ^6.8 Hz, 3H), 0.90 (d, J = ^6.8 Hz, 3HLC-MS: m/z 399.22 [M +H]+ Purity by HpLC: 94.03% (220nm) and purity by chiral HPLC is 98.99% (229nm).

Example 226. (4-Fluorotetrahydro-2H-pyran-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate ( 6-226)

This compound was prepared from (4-fluorotetrahydro-2H-pyran-4-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400MHz, DMSO-d ⁶ ) : ⁸ 9.03 (s, 1H), 8.58 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.3 Hz, 1H), 4.97 (s, 2H ), 4.35 (t, J = 7.3 Hz, 1H), 4.29-4.14 (m, 2H), 3.73 (td, J = 11.5, 3.8 Hz, 2H), 3.56 (dt, J =3.9, 10.8 Hz, 2H) , 2.47 (s, 3H), 2.16 (qd, J = 13.6, 6.7 Hz, 1H), 1.91 -1.69 (m, 4H), 0.97 (dd, J = ^{6 8} 3.4 Hz, ^6H.); LC-MS: m/z 408.23 [M+H)+ HPLC purity: 99.40% (220 nm) and chiral HPLC purity is 98.37% (210 nm).

Example 227. (1,4-dioxan-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6- 227)

This compound was prepared from (1,4-dioxan-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400MHz, DMSO-d ⁶ ): ⁸ 9.03 (s, 1H), 8.54 (d, J = 7.8 Hz, 1H), 7.38 (d, J =7.3 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H) , 4.36-4.27 (m, 1H), 4.17-3.98 (m, 2H), 3.78-3.69 (m, 3H), 3.66 - 3.52 (m, 2H), 3.51 - 3.40 (m, 1H), 3.38-3.33 ( m, 1H), 2.47 (s, 3H), 2.21 -2.08 (m, 1H), 0.97 (d, J = ^{6 6} Hz, 3H), 0.95 (d, J = ^{6 6} Hz, ^3H).; LC-MS: m/z 392.22 [M+H]+. HPLC purity: 99.17% (220nm).

Example 228. Cyclopentylmethyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate (228)

This compound was prepared from cyclopentylmethyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-da): 89.05 (s, 1H), 8.12 (d, J = 8.3 Hz, 1H), 7.41 (d, J =7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.74 (s, 1H), 4.40 (d, J = 7.8 Hz, 1H), 4.06 - 3.77 (m, 2H), 2.49 (d, J = 5.4 Hz, 3H), 2.24 - 2.02 (m, 1H), 1.78 - 1.65 (m, 2H), 1.62 - 1.45 (m, 4H), 1.25 (d, J = 2.9 Hz, 8H); LC-MS: m/z 390.24 [M+H]+. HPLC purity is 98.87% (220nm) and chiral HPLC purity is 99.5% (227nm).

Example 229. (1-Hydroxycyclohexyl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-229)

This compound was prepared from (1-hydroxycyclohexyl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300MHz, DMSO-d6): 89.04 (s, 1H), 8.50 (d, J = 8.1 Hz, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 8.1 Hz, 1H), 4.97 (s, 2H), 4.40 (dd, J = 6.6, 8.1 Hz, 1H), 4.32 (s, 1H), 3.87 (s, 2H), 2.47 (s, 3H), 2.18 (br dd, J = 13.4, 6.8, Hz, 1H), 1.67 - 1.32 (m, 9H ), 1.17 (br d, J = 11.0 Hz, 1H), 0.97 (d, J = 7.0 Hz, 3H), 0.96 (d, J = 7.0 Hz, 3H); LC-MS: m/z 404.27 [M+H]+ HPLC purity: 99.19% (220 nm) and chiral HPLC purity is 96.91% (210 nm).

Example 230 Pyridin-2-ylmethyl(S)-3-hydroxy-2-1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate (6 -230)

This compound was prepared from pyridin-2-ylmethyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (300 MHz, DMSO- d6): 89.05 (br s, 1H), 8.55 (br d, J = 4.4 Hz, 1H), 8.29 (d, J = 8.1 Hz, 1H), 7.82 (dt, J = 7.7, 1.8 Hz, 1H), 7.60-7.47 (m, 1H), 7.45-7.32 (m, 2H), 7.25 (d, J = 7.7 Hz, 1H), 5.37 - 5.16 (m, 2H), 5.04 - 4.82 (m, 3H), 4.53 ( d, J = 8.1 Hz, 1H), 2.45 (s, 3H), 1.27 (d, J = 4.4 Hz, 6H) LC-MS: m/z 399.25 [M+H]+. HPLC purity: 93.98% (220nm) and chiral HPLC purity is 96.7% (210nm).

Example 231.2-(6-oxa-3-azabicyclo[3.1.1]heptan-3-yl)ethyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl )-L-valinate (6-231)

This compound was prepared from 6-oxa-3-azabicyclo[3.1.1]heptane in a similar manner to the last step of Example 214. 1H NMR (300 MHz, DMSO-d6): 89.03 (br s, 1H) , 8.51 (d, J = 7.7 Hz, 1H), 7.37 (d, J =8.1 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 4.97 (s, 2H), 4.40 (d, J = 5.9 Hz, 2H), 4.35-4.28 (m, 2H), 4.25-4.15 (m, 1H), 3.06 ( br d, J =11.0 Hz, 2H), 2.87 - 2.76 (m, 3H), 2.74 - 2.61 (m, 2H), 2.47 (s, 3H), 2.24 - 2.02 (m, 2H), 0.96 (d, J = 6.6Hz, 6H); LC-MS: m/z 417.31 [M+H]+. HPLC purity: 95.6% (220nm) and chiral HPLC purity is 95.17% (215nm).

Example 232. (6-(dimethylamino)pyrazin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -232)

This compound was prepared from (6-(dimethylamino)pyrazin-2-yl)methyl-L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6) : 89.04 (s, 1H), 8.64 (br d, J =7.7 Hz, 1H), 8.33 (d, J = 4.8 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.24 (d, J = 7.7 Hz, 1H), 6.63 (d, J = 4.8 Hz, 1H), 5.04 (s, 2H), 4.97 (s, 2H), 4.44 (t, J = 7.3 Hz, 1H), 3.10 (s, 6H ), 2.46 (s, 3H), 2.22 (br dd, J = 6.8, 13.4 Hz, 1H), 0.99 (d, J = 6.6 Hz, 6H); LC-MS: m/z 427.27 [M+H]+. HPLC purity: 98.46% (220nm), 98.32% (254nm) and chiral HPLC purity is 99.61% (244nm).

Example 233. (3-methyltetrahydrofuran-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-233)

This compound was prepared from (3-methyltetrahydrofuran-3-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.04 (s, 1H), 8.55 (br d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.97 (s, 2H), 4.37 - 4.27 (m, 1H), 4.05 - 3.92 (m, 2H), 3.75 (t, J = 7.2 Hz, 2H), 3.57 (dd, J = 8.4, 5.1 Hz, 1H), 3.29 - 3.22 (m, 1H), 2.48 (s, 3H), 2.22 - 2.06 (m, 1H), 1.89 - 1.71 (m, 1H), 1.66 - 1.50 (m, 1H), 1.10 (s, 3H), 1.01 - 0.84 (m, 6H); LC-MS: m/z 390.3 [M+H]+. HPLC purity: 96.4% (220nm).

Example 234. ((R)-tetrahydrofuran-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 234 )

This compound was prepared from ((R)-tetrahydrofuran-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.04 (s, 1H), 8.54 (d, J = 7.7 Hz, 1H), 7.37 (d, J = 7.7 Hz, 1H), 7.25 (d, J = 7.7 Hz, 1H), 4.98 (s, 2H), 4.30 (t, J = 7.2 Hz, 1H), 4.15-3.91 (m, 2H), 3.82-3.54 (m, 3H), 3.45 (dd, J = 8.6, 5.7 Hz, 1H), 2.57 - 2.51 (m, 1H ), 2.47 (s, 3H), 2.14 (qd, J = 13.5, 6.6 Hz, 1H), 2.01 - 1.85 (m, 1H), 1.58 (dt, J = 13.1, 6.8 Hz, 1H), 0.96 (dd, J = 6.8, 1.7Hz, 6H); LC-MS: m/z 376.24 [M+H]+. HPLC purity: 96.3% (220nm) and chiral HPLC purity is 97.66% (210nm).

Example 235. ((S)-tetrahydrofuran-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 235 )

This compound was prepared from ((S)-tetrahydrofuran-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-da): 89.04 (s, 1H), 8.53 (d, J = 7.3 Hz, 1H), 7.37 (d, J = 7.3 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 4.97 (s, 2H), 4.34 -4.27 (m, 1H), 4.11 -3.95 (m, 2H), 3.79-3.69 (m, 2H), 3.65 - 3.58 (m, 1H), 3.44 (dd, J = 8.8, 5.9 Hz, 1H), 2.57 - 2.51 (m, 1H), 2.47 (s, 3H), 2.14 (qd, J = 13.3, 6.8 Hz, 1H), 2.02 - 1.90 (m, 1H), 1.64 - 1.53 (m, 1H), 0.98 (d , J = 6.8 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H); LC-MS: m/z 376.24 [M+H]+; HPLC purity: 99.29% (220nm) and chiral HPLC purity is 97.79% (215nm).

Example 236. (5-(trifluoromethyl)pyrimidin-2-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -236)

This compound was prepared from (5-(trifluoromethyl)pyrimidin-2-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6): 89.29 (s, 2H), 9.02 (s, 1H), 8.58 (d, J = 7.8 Hz, 1H), 7.39 (d, J = 7.8 Hz, 1H), 7.24 (d, J = 7.3 Hz, 1H), 5.44 (q, J =15.2 Hz, 2H), 4.97 (s, 2H), 4.51 (dd, J = 7.8, 6.4 Hz, 1H), 2.46 (s, 3H), 2.28 (qd, J = 13.5, 6.8 Hz , 1H), 1.03 (dd, J = 6.6, 4.6 Hz, 6H); LC-MS: m/z 452.16 [M+H]+. HPLC purity: 98.97% (220nm) and chiral HPLC purity is 99.74% (215nm).

Example 237. (2-aminopyrimidin-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 237)

This compound was prepared from (2-aminopyrimidin-4-yl)methyl L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (400 MHz, DMSO-d6): 89.03 (s , 1H), 8.64 (br d, J = 7.8 Hz, 1H), 8.23 (d, J = 5.4 Hz, 1H), 7.38 (d, J = 7.3 Hz, 1H), 7.25 (br d, J = 7.3 Hz , 1H), 6.76-6.57 (m, 3H), 5.11 -4.91 (m, 4H), 4.42 (brt, J =7.1 Hz, 1H), 2.46 (s, 3H), 2.29 - 2.15 (m, 1H), 0.99 (br d, J = 6.4 Hz, 6H); LC-MS: m/z 399.22 [M+H]+. HPLC purity: 97.35% (220 nm) and chiral HPLC purity is 99.97% (222 nm).

Example 238. 2-morpholinoethyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)-3-methylbutanoate ( 6-238)

This compound was prepared from 2-morpholinoethyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04 in a similar manner to the last step of Example 1,1H NMR (400 MHz, DMSO-da ): 89.05 (s, 1H), 8.13 (s, 1H), 7.41 (d, J =7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.42 (m , 2H), 4.20 (br s, 1H), 4.18 (br s, 1H), 3.54 (s, 4H), 2.60-2.32 (m, 9H), 1.26 (d, J = 6.4 Hz, 6H); LC-MS: m/z 421.27 [M+H]+. HPLC purity: 96.83% (220nm) and chiral HPLC purity is 98.10% (210nm).

Example 239. ((R)-tetrahydrofuran-2-yl)methyl (S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6 -carboxamido)-3-methylbutanoate (6-239)

This compound was prepared from ((R)-tetrahydrofuran-2-yl)methyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04 in a similar manner to the last step of Example 11H NMR (400 MHz, DMsO-d6): 89.05 (s, 1H), 8.13 (d, J = 7.6 Hz, 1H), 7.41 (d, J =7.6 Hz, 1H), 7.26 (d, J = 8 Hz, 1H), 4.98 (s, 2H), 4.74 (s, 1H), 4.42 (d, J = 8.4 Hz, 1H), 4.12 (m, 1H), 4.08 - 3.98 (m, 2H), 3.76 (m, 1H ), 3.65 (m, 1H), 2.50 (m, 3H), 1.95 - 1.75 (m, 3H), 1.61 (m, 1H), 1.20 (m, 6H); LC-MS: m/z 392.22 [M+H]+. HPLC purity: 98.71% (220nm) and chiral HPLC purity is 94.97% (210nm).

Example 240. (2-(methylamino)pyrimidin-4-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 -240)

This compound was prepared from (2-(methylamino)pyrimidin-4-yl)methyl-L-valinate and Acid-04 in a similar manner to the last step of Example 1. 1H NMR (300 MHz, DMSO-d6) : 89.04 (s, 1H), 8.64 (d, J =7.8 Hz, 1H), 8.27 (br d, J = 4.2 Hz, 1H), 7.38 (d, J = 7.8 Hz, 1H), 7.25 (d, J = 7.8 Hz, 1H), 7.11 (m, 1H), 6.61 (d, J = 4.8 Hz, 1H), 5.01 (s, 2H), 4.97 (s, 2H), 4.42 (t, J = 7.2 Hz, 1H ), 2.78 (d, J = 4.8 Hz, 3H), 2.46 (s, 3H), 2.22 (m, 1H), 0.98 (d, J = 6.6 Hz, 6H); LC-MS: m/z 413.18 [M+H]+. HPLC purity: 98.37% (220nm) and chiral HPLC purity is 96.6% (210nm).

Example 241. (Tetrahydro-2H -pyran-4-yl)methyl (6-241)

This compound was prepared from (tetrahydro-2H-pyran-4-yl)methyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04 in a similar manner to the last step of Example 11H NMR (300 MHz, DMSO-d6): 89.05 (s, 1H), 8.17 (d, J = 8.7 Hz, 1H), 7.41 (d, J =7.8 Hz, 1H), 7.26 (d, J = 7.8 Hz, 1H), 4.98 (s, 2H), 4.75 (s, 1H), 4.42 (d, J = 8.7 Hz, 1H), 3.96 (d, J =6.6 Hz, 2H), 3.84 (m, 2H), 3.26 ( d, J =10.5 Hz, 2H), 2.45 (m, 3H), 1.87 (m, 1H), 1.62 - 1.58 (m, 2H), 1.33 -1.20 (m, 8H); LC-MS: m/z 406.22 [M+H]+. HPLC purity: 98.28% (220nm) and chiral HPLC purity is 99.48% (210nm)

Example 242. 3-Fluoro-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-242)

This compound was prepared from methyl 3-fluoro-4-hydroxybanzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163. 1H NMR (400 MHz, DMSO-d e ): 89.03 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.27-7.18 (m, 2H), 7.17-7.16 (m, 2H), 5.10 (dd, J = 12.0 Hz, 20.0 Hz, 2H), 4.97 (s, 2H), 4.33 (t, J = 8.0 Hz, 1H), 4.14 (t, J = 4.0 Hz, 2H), 2.79 (t, J = 8.0 Hz, 2H), 2.50 (s, 3H), 2.49-2.13 (m, 1H), 1.69-1.66 (m, 4H), 0.95 (d, J = 8.0 Hz, 3H), 0.91 (d, J = 8.0Hz, 3H); ESI-MS m/z 513 [M+H]+; HPLC purity: 98.20% (220nm), 94.25% (254nm).

Example 243. 3-Chloro-4-(2-(pyrrolidin-1-yl)ethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-243)

This compound was prepared from methyl 3-chloro-4-hydroxybanzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163. 1H NMR (400 MHz, DMSO-d e ): 89.03 (s, 1H), 8.56 (d, J =7.6 Hz, 1H), 7.47 (d, J =1.6 Hz, 1H), 7.35-7.33 (m, 1H), 7.33-7.31 (m, 1H), 7.23 (d, J =7.6 Hz, 1H), 7.16 (d, J = 8.4 Hz, 1H), 5.14-5.06 (m, 2H), 4.97 (s, 2H), 4.33 (t, J = 7.2 Hz, 1H) , 4.15 (t, J = 6.0 Hz, 2H), 2.81 (t, J = 5.6 Hz, 2H), 2.56-2.52 (m, 4H), 2.44 (s, 3H), 2.14 (q, J = 6.8, 13.6 Hz, 1H), 1.72-1.64 (m, 4H), 0.93 (dd, J =1.2 Hz, 7.2 Hz, 6H); ESI-MS m/z 529 [M+H]+; HPLC purity: 98.38% (220nm), 94.90% (254nm).

Example 244. 4-Chloro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-244)

This compound was prepared from methyl 4-chloro-3-hydroxybanzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163. 1H NMR (400 MHz, DMSO-d e ): 89.05 (s, 1H), 8.61 (d, J =7.6 Hz, 1H), 7.42 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 7.19 (s, 1H), 7.00-6.98 (m, 1H), 5.18 (s, 2H), 4.98 (s, 2H), 4.35 (t, J = 7.2 Hz, 1H), 4.12 (t , J = 4.2 Hz, 2H), 2.79 (t, J = 5.6 Hz, 2H), 2.54-2.53 (m, 4H), 2.45 (s, 3H), 2.20-2.14 (m, 1H), 1.68 1.65 (m , 4H), 0.96 (dd, J = 3.6, 3.2 Hz, 6H); ESI-MS m/z 529 [M+H]+; HPLC purity: 96.52% (220nm), 95.91% (254nm).

Example 245. 4-Fluoro-3-(2-(pyrrolidin-1-yl)ethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-245)

This compound was prepared from methyl 4-fluoro-3-hydroxybanzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163.1H NMR (400 MHz, DMSO-cfe): 59.03 ( s, 1H), 8.58 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.24-7.17 (m, 3H), 6.97-6.96 (m, 1H), 5.14 (d , J = 2.0 Hz, 2H), 4.97 (s, 2H), 4.35-4.31 (m, 1H), 4.09 (t, J = 6.0 Hz, 2H), 2.76 (t, J = 6.0 Hz, 2H), 2.49 -2.46 (m, 4H), 2.43 (s, 3H), 2.19-2.10 (m, 1H), 1.66-1.64 (m, 4H), 0.95 (dd, J = 3.2, 6.4 Hz, 6H); ESI-MS m/z 513 [M+H]+; HPLC purity: 98.72% (220nm), 100% (254nm).

Example 246. 3-Fluoro-4-(3-(pyrrolidin-1-yl)propoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl) -L-valinate (6-246)

This compound was prepared from methyl 4-fluoro-3-hydroxybanzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163.1H NMR (400 MHz, DMSOC): 59.05 (s, 1H), 8.56 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.27-7.21 (m, 2H), 7.16-7.15 (m, 2H), 5.00 (q, J = 12.0 Hz, 2H), 4.97 (s, 2H), 4.33 (t, J = 8.0 Hz, 1H), 4.09 (t, J =8.0 Hz, 2H), 2.43 (s, 3H), 2.16-2.11 (m , 1H), 1.90 (t, J = 4.0 Hz, 2H), 1.68 (s, 4H), 0.93 (dd, J =8.0, 4.0 Hz, 6H); ESI-MS m/z 527 [M+H]+; HPLC purity: 96.19% (220nm), 91.57% (254nm).

Example 247. 4-(2-Morpholinoethoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6 247)

This compound was prepared from methyl 4-(2-morpholinoethoxy)benzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163. 1H NMR (400 MHz, DMSOC): 59.03 ( s, 1H), 8.53 (d, J =8.0 Hz, 1H), 7.34-7.31 (m, 3H), 7.23 (d, J =8.0 Hz, 1H), 6.94 (d, J = 8.4 Hz, 2H), 5.14-5.04 (m, 2H), 4.97 (s, 2H), 4.32 (t, J =7.2 Hz, 1H), 4.08 (t, J = 6.0 Hz, 2H), 3.57 (t, J = 4.0 Hz, 4H ), 2.68 (t, J = 5.6 Hz, 2H), 2.45 (d, J = 4.4 Hz, 4H), 2.43 (s, 3H), 2.15-2.07 (m, 1H), 0.92-0.91 (m, 6H) ; ESI-MS m/z 511 [M+H]+; HPLC purity: 95.94% (220nm), 97.37% (254nm).

Example 248. (4,4-difluorocyclohexyl)methyl(S)-3-hydroxy-2-(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carboxamido)- 3-methylbutanoate (6-248)

This compound was prepared from (4,4-difluorocyclohexyl)methyl (S)-2-amino-3-hydroxy-3-methylbutanoate and Acid-04 in a similar manner to the last step of Example 1.1H NMR (300 MHz, DMSO-d6): 57.41 (d, J = 8 Hz, 1H), 7.27 (d, J = 8 Hz, 1H), 4.98 (s, 2H), 4.41 (s, 1H), 3.99 (d, J = 5.6 Hz, 2H), 2.48 (s, 3H), 2.1-1.95 (m, 3H), 1.90 -1.70 (m, 6H), 1.32 - 1.23 (m, 8H); LC-MS: m/z 440.35 [M+H]+. HPLC purity: 99.59% (220nm) and chiral HPLC purity is 99.54% (210nm).

Example 249. 4-(3-(Pyrrolidin-1-yl)propoxy)benzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-249)

This compound was prepared from methyl 4-(3-(pyrrolidin-1-yl)propoxy)benzoate, N-Boc-(S)-valine, and Acid-04 in a similar manner to Example 163. 1H NMR (400 MHz, DMSO-cfe): 89.04 (s, 1H), 8.52 (d, J = 7.6 Hz, 1H), 7.34-7.30 (m, 3H), 7.22 (d, J =8.0 Hz, 1H), 6.91 (d , J = 8.8 Hz, 2H), 5.13-5.04 (m, 2H), 4.97 (s, 2H), 4.33-4.30 (m, 1H), 4.02-3.99 (m, 2H), 2.53-2.52 (m, 2H ), 2.43-2.41 (m, 7H), 2.15-2.10 (m, 1H), 1.90-1.85 (m, 2H), 1.69-1.65 (m, 4H), 0.92 (d, J = 6.8 Hz, 6H); ESI-MS m/z 509 [M+H]+; HPLC purity: 96.08% (220nm), 96.68% (254nm).

Example 250. (3-Hydroxytetrahydrofuran-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate (6-250)

This compound was prepared from (3-hydroxytetrahydrofuran-3-yl)methyl-L-valinate and Acid-04 in a similar manner to the last step of Example 1.1 H NMR (400 MHz, DMSO-d6): 89.05 (s , 1H), 8.51 (d, J = 7.8 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 7.24 (d, J =8.0 Hz, 1H), 5.07 (s, 1H), 4.98 (s , 2H), 4.39 (m, 1H), 4.12 (m, 2H), 3.90- 3.70 (m, 2H), 3.63 (dd, J = 8.8 Hz, 1H), 3.5 (d, J = 8.0 Hz, 1H) , 2.50 (m, 3H), 2.23-2.1 (m, 1H), 1.97- 1.87 (m, 1H), 1.84- 1.75 (m, 1H), 0.96 (m, 6H); LC-MS: m/z 392.25 [M+H]+. HPLC purity: 98.1% (220nm).

Example 251. (5-Fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L -valinate (6-251)

To a solution of 5-bromo-2-chloro-3-fluoropyridine (17.0 g, 65.3 mmol) in THF (200 mL) was added i-PrMgClLiCl (1.3 M, 60 mL) dropwise at 0°C over a period 30 min under N ² . The mixture was stirred at 15°C for 2h. Methyl chloroformate (15.4 g, 163 mmol) was then added dropwise at 0°C over a period of 30 minutes. The mixture was stirred at 15°C for 11h. The reaction was quenched with water (100 mL) slowly, then extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL x 2), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo. The residue was purified by column chromatography (SO ² , petroleum ether/ethyl acetate = 100:1 to 50:1) to give methyl 6-chloro-5-fluoronicotinate (5.00 g, 32%) as a white solid. .

To a solution of 6-chloro-5-fluoronicotinate (5.00 g, 26.4 mmol) in acetonitrile (100 mL) TMSCI (5.73 g, 52.8 mmol) was added. The mixture was stirred at 50°C for 55 minutes. The mixture was then cooled to 15°C and poured into a solution of Nal (39.54 g, 263.8 mmol) in acetonitrile (100 mL) in one portion. The mixture was stirred at 15°C for 5 minutes. The mixture was filtered and quenched by saturated Na ² S ² O ³ solution (100 mL), then extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated in vacuo. The residue was purified by recrystallization from MTBE (30 mL) to give 5-fluoro-6-iodonicotinate (3.00 g, 40%) as a yellow solid.

A mixture of methyl 5-fluoro-6-iodonicotinate (1.50 g, 5.34 mmol), methyl 2,2-difluoro-2-fluorosulfonyl-acetate (5.13 g, 26.7 mmol), HMPA (2.87 g, 16.0 mmol), and Cul ( 3.05 g, 16.0 mmol) in DMF (15 mL) was stirred at 80°C for 12 h under N ² atmosphere. The reaction was quenched with water (30 mL) slowly, then extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (50 mL), dried over ^{anhydrous Na 2} SO ⁴ , filtered and concentrated to empty. The residue was purified by column chromatography (SIO ² , petroleum ether/ethyl acetate = 50:1 to 20/1) to give 5-fluoro-6-trifluoromethylnicotinate (470 mg, 35%) as an off-white solid.

To a solution of methyl 5-fluoro-6-trifluoromethylnicotinate (440 mg, 1.97 mmol) in THF (2 mL) was added LAH (75 mg, 1.97 mmol) at -20°C. The mixture was stirred at -20°C for 5 min. The reaction was quenched by saturated sodium potassium tartrate (1 mL), filtered and concentrated in vacuo to give (5-fluoro-6- (trifluoromethyl)pyridin-3-yl)methanol (280 mg, 73%) a colorless oil.

(5-Fluoro-6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate se was prepared from (5-fluoro-6-(trifluoromethyl)pyridin-3-yl)methanol, N-Boc-(S)-valine and Acid-04 in a similar manner to Example 1. 1H NMR (400 MHz, DMSO -de) 9.03 (s, 1H), 8.67-8.65 (m, 2H), 8.15 (d, J = 8.0 Hz, 1H), 7.35 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 1H), 5.38 (q, J = 8.0 Hz, 2H), 4.97 (s, 2H), 4.39 (t, J = 8.0 Hz, 1H), 2.42 (s, 3H), 2.22-2.17 (m, 1H ), 0.97 (d, J = 8.0 Hz, 6H);

ESI-MS m/z 469 [M+H]+; HPLC purity: 99.10% (220nm), 97.74% (254nm).

Example 252. In vitro Alamar Blue 72-h drug susceptibility assay for T. congolense

Compounds were tested in vitro for chemotherapeutic potency against T. congolense strain IL3000 (drug-susceptible), using the Alamar Blue assay with various modifications. Test compounds were prepared as 10 mg/ml DMSO stocks for each assay run. Compounds were tested in at least three separate independent test cycles and an 11-point dilution curve was used to determine IC ⁵⁰ values. Bloodstream form trypanosomes were supported in HMI medium containing 20% bovine serum and incubated with test compounds for 69 h at 34°C in a humidified atmosphere containing 5% ^{CO 2 .} Then 10 μl of resazurin dye (12.5 mg in 100 ml phosphate buffered saline, Sigma-Aldrich, Buchs, Switzerland) was added for a further 3 h. Plates were then read using a fluorescent plate reader (Spectramax, Gemini XS, Bucher Biotec, Basel, Switzerland) using an excitation wavelength of 536nm and an emission wavelength of 588nm. Data points were averaged to generate sigmoid dose-response curves and IC ⁵⁰ values were determined using Softmax Pro 5.2 software.

The results are shown in Table 1. Compounds have an activity designated "A" given an IC ⁵⁰ ^0.5 nM; compounds having an activity designated "B" gave an IC ⁵⁰ of 0.51-9.99 nM; and compounds having an activity designated "C" gave an IC ⁵⁰ of 10-5,000 nM.

Example 253. Ex vivo Alamar Blue 48-h Drug Susceptibility Assay for T. vivax

Compounds were tested ex vivo for chemotherapeutic potency against T. vivax strain STIB719/ILRAD560 (drug-susceptible), using the Alamar Blue assay with various modifications. Test compounds were prepared as 10 mg/ml DMSO stocks for each assay run. Compounds were tested in at least three separate independent test runs and an 11-point dilution curve was used to determine ¹ C ⁵⁰ values. Trypanosomes in the bloodstream form were propagated and harvested from a highly parasitemic mouse (via cardiac puncture) and incubated with test compounds for 45 hours at 37°C in a humidified atmosphere containing 5% CO ² , supported on HMI medium containing 20% bovine serum. Then 10 μl Resazurin dye (12.5 mg in 100 ml phosphate buffered saline, Sigma-Aldrich, Buchs, Switzerland) was added for a further 3 hours. Plates were then read using a fluorescent plate reader (Spectramax, Gemini XS, Bucher Biotec, Basel, Switzerland) using an excitation wavelength of 536nm and an emission wavelength of 588nm. Data points were averaged to generate sigmoid dose-response curves and IC ⁵⁰ values were determined using Softmax Pro 5.2 software.

The results are shown in Table 1. Compounds have an activity designated "A" given an IC ⁵⁰ ^0.5 nM; compounds having an activity designated "B" gave an IC ⁵⁰ of 0.51-49.9 nM; compounds having an activity designated "C" gave an IC ⁵⁰ of 50-2,000 nM; and compounds having an activity designated "D" gave an IC ⁵⁰ > 2,000 nM.

Example 254. Measurement of the ^{in vitro IC 50} of death of T. cruzi amastigote using TdTomato-modified T. cruzi

The T. cruzi parasites used in this assay were genetically modified to express TdTomato fluorescent protein. Vero cells (African green monkey kidney epithelial cells) were harvested from continuous cultures using trypsin and added to the inner 60 wells of Greiner Bio One 96-well plates (plate catalog # 655090) at 200 ul/well 2.5 x 106 cells/ml. Cells were allowed to adhere for 1 h prior to infection with T. cruzi. T. cruzi were harvested for infection from previously infected Vero cells, washed, pelleted and resuspended at 5 x 106/ml. 50ul of parasites were added to each well containing Vero cells. Compounds were prepared from 5 mM stock concentrations in DMSO to final concentrations in wells ranging from 5 uM to 5 nM. Wells were provided for negative controls, which lacked compounds. Plates were placed in a 37°C incubator for 20 min, then a "Day 0" reading was taken on a Synergy H4 plate reader to record initial levels of fluorescence, at 544 (excitation) and 612 nm (emission). 96-well plates were placed in Tupperware containers with moist paper towels and incubated at 37°C in an incubator for 72 h. After 72 h, plates were read again (reading on day 3) and data analyzed using Excel and/or Graphpad software. Day 0 fluorescence was subtracted from day 3 to remove input parasite fluorescence. Growth curves are generated and inhibitory concentrations of 50% and 90% are determined by non-linear regression analysis.

The results are shown in Table 1. Compounds have an activity designated "A" given an IC ⁵⁰ ^20 nM; compounds having an activity designated "B" gave an IC ⁵⁰ of 21-999 nM; and compounds having an activity designated "C" gave an IC of ⁵⁰ ^1,000 nM.

Table 1 shows the activity of selected compounds of this disclosure in the assays discussed in Examples 252-254, where each compound number corresponds to the compound numbering set forth in Examples 1-251 herein, supra.

Table 1

Claims (15)

1. A compound selected from the group consisting of: (6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; 4.4-difluorocidohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; Y tetrahydro-2H-pyran-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 2. The compound of claim 1, wherein the compound is (6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 3. The compound of claim 1, wherein the compound is 4-fluorobenzyl (1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 4. The compound of claim 1, wherein the compound is 4.4-difluorocyclohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 5. The compound of claim 1, wherein the compound is tetrahydro-2H-pyran-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 6. A pharmaceutical composition comprising a compound of any of claims 1 to 5. 7. A compound for use in medicine, the compound being a compound of any one of claims 1 to 5. 8. A compound for use in the treatment of a parasitic disease selected from the group consisting of: (6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; 4-fluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; 4.4-difluorocyclohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; Y tetrahydro-2H-pyran-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 9. The compound for use according to claim 8, wherein the compound is (6-(trifluoromethyl)pyridin-3-yl)methyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 10. The compound for use according to claim 8, wherein the compound is 4-fluorobenzyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 11. The compound for use according to claim 8, wherein the compound is 4.4-difluorocyclohexyl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 12. The compound for use according to claim 8, wherein the compound is tetrahydro-2H-pyran-4-yl(1-hydroxy-7-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-6-carbonyl)-L-valinate; or a pharmaceutically acceptable salt thereof. 13. A compound for use according to any of claims 8-12, wherein the parasitic disease involves a parasite selected from: Trypanosoma cruzi, Trypanosoma congolense, Trypanosoma vivax and Trypanosoma evansi. 14. A compound for use according to any of claims 8-12, wherein the parasitic disease is trypanosomiasis. 15. A compound for use according to any of claims 8-12, wherein the parasitic disease is African animal trypanosomiasis.